TWI662031B - Crystals of 1- ｛2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzylpyrene-3-azetidinecarboxylic acid type - Google Patents

Abstract

The invention discloses a drug for a disease or disorder mediated by the S1P1 receptor. 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl The crystalline form of] -benzyl} -3-azetidinecarboxylic acid. The invention also discloses a method for preparing the crystal form, a pharmaceutical composition thereof, and a use thereof for preparing a medicament for treating and / or preventing a disease or condition mediated by the S1P1 receptor.

Description

Crystals of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid type

The present application belongs to the technical field of medicinal chemical crystallization. Specifically, a drug involving a disease or disorder mediated by the S1P1 receptor 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 The crystalline form of -yl] -benzyl} -3-azetidinecarboxylic acid also relates to a method for preparing the crystalline form, a pharmaceutical composition thereof and use thereof.

Polymorphs are properties of some molecules and molecular compositions. The same molecule may form different crystals due to different arrangements. The polymorphs have different crystal structures and physical properties, such as solubility, stability, thermal properties, mechanical properties, purification ability, X-ray diffraction pattern, infrared absorption pattern, Raman spectrum, and solid-state nuclear magnetic resonance. One or more analytical methods can be used to distinguish different crystalline forms of the same compound.

Discovery of new crystalline forms of pharmaceutically active ingredients (including anhydrous, hydrate, solvate) can provide materials with advantageous processing properties, discovery of new crystalline forms and solvates can provide materials with better physical and chemical properties, such as better The bioavailability, storage stability, easy processing, easy purification or as an intermediate crystal form that promotes conversion to other crystal forms. New crystalline forms of pharmaceutically useful compounds may also indicate improved drug performance. It expands the options available to formulation scientists to optimize formulation performance Types of raw materials, such as improved dissolution, improved shelf life, and easier processing.

1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid has S1P1 Receptor agonist activity and selection specificity, and has significantly reduced half-life in vivo, so it is a high-quality second-generation S1P1 receptor agonist. Numerous studies have shown that there are a variety of S1P1 receptor agonists that are able to bind to homologous receptors expressed on lymphocytes and cause internalization of the S1P1 receptor, which in turn prevents lymphocyte export. Therefore, the S1P1 receptor agonist can reduce the body's ability to initiate an immune response by preventing the transport of lymphocytes, and thus can be used as an immunosuppressant to treat various autoimmune diseases. Chemical formula of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid C ₂₃ H ₂₄ FN ₃ O ₃ ; molecular weight 409.45; chemical structure is shown below:

Patent document CN103450171A (which is incorporated herein by reference) discloses 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadioxane Identification, preparation, composition and use of azole-3-yl] -benzyl} -3-azetidinecarboxylic acid. Specifically, a method for preparing such a compound is disclosed in Example 2.

In view of the shortcomings of the existing technology, the study of 1- {2-fluoro-4- [5- (4-isobutyl The crystalline form of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid has very important practical significance.

The object of the present invention is to provide 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl The crystalline form and amorphous form of butidine carboxylic acid, and its preparation method, its pharmaceutical composition and use are provided.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The crystalline form I of 3-azetidincarboxylic acid (hereinafter referred to as "crystalline form I") and a method for preparing the same, the crystalline form I is a hemihydrate.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I at a diffraction angle 2θ of 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 ° and There are characteristic peaks at 18.6 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form I is 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 10.1 ± 0.2 °, 11.1 ± 0.2 °, 12.1 ± There are characteristic peaks at 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 °, 18.6 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 °, and 27.0 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form I has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form I is shown in FIG. 1.

The crystal form I also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form I is shown in FIG. 5.

The crystal form I is prepared by any one of the following methods: (1) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidinecarboxylic acid forms a suspension in the following solvent system, stirs and crystallizes, separates and separates the precipitated crystals to obtain 1- {2-fluoro-4- [ Form 5- of 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, wherein the solvent system is selected from Water or a mixture of water and an organic solvent selected from the group consisting of C ₁ to C ₄ alcohols, C ₅ to C ₆ ethers, C ₃ to C ₄ ketones, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethylarsine, C ₇ alkanes, and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, propanol, butanol, and methyltrioxane. Grade butyl ether, isopropyl ether, acetone, methyl ethyl ketone, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethyl sulfene, methyl Cyclohexane or n-heptane; preferably, the volume content of water in the mixture of water and organic solvent is at least 0.01%, more preferably Less than 0.1%; preferably, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The amount of 3-azetidinecarboxylic acid is 1.1 to 50 times, more preferably 1.5 to 10 times its solubility in the solvent system at the operating temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the operating temperature is room temperature; preferably, the crystallization time is 3-14 days, more preferably 3-7 days; (2) a certain temperature In the following, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinylcarboxyl The acid forms a solution in a mixed system of water and tetrahydrofuran, cools and stirs the crystals, and separates the precipitated crystals to dryness to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 Crystalline form I of 2,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid; preferably, the volume content of water in the mixed system of water and tetrahydrofuran is 0.01% ~ 50%, more preferably 0.1% ~ 50%; preferably, in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- The amount of oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 0.1 ~ its solubility in the mixed system at a certain temperature 1 time, more preferably 0.5 to 1 time; preferably, the certain temperature is 40 ° C to 50 ° C; preferably, the temperature after cooling is room temperature; preferably, the crystallization time is 0.5 ~ 72 hours, more preferably 0.5 ~ 10 hours; (3) To 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidinecarboxylic acid in a solution formed in an organic solvent is added with water, the crystals are stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, Form I, wherein the organic solvent is selected from the group consisting of ethanol And trifluoroethanol mixture, tetrahydrofuran, 1,4-dioxane, dimethylarsine or a mixture thereof; preferably, the organic solvent is selected from a trifluoroethanol solution of ethanol (the volume content of ethanol is 66%) , Tetrahydrofuran, 1,4-dioxane or dimethylarsine; preferably, the volume ratio of the water to the organic solvent is 1: 1 to 50: 1, more preferably 1: 1 to 10: 1; Preferably, in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The amount of 3-azetidincarboxylic acid is the amount of 0.1 to 1 times the solubility in a solvent; more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably Room temperature; preferably, the crystallization time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (4) 1- {2-fluoro-4- [5- (4-isobutylbenzene) Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in a mixed system of water and organic solvent, evaporating and crystallizing, separating the precipitated crystals, Drying to give 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxyl Form I of the acid; wherein the organic solvent is selected from the group consisting of isopropanol, acetone, tetrahydrofuran, or a mixture thereof; preferably, the organic solvent is selected from the group consisting of isopropanol, acetone, or tetrahydrofuran; preferably, the water and The volume content of water in the mixture of organic solvents is 0.01% to 50%, more preferably at least 0.1% to 50%; preferably, 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the solvent system at the operating temperature, and more It is preferably 0.5 to 1 times; preferably, The operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 1 to 7 days, more preferably 3 ~ 7 days; in the above-mentioned preparation method of (1) ~ (4) crystal form I, the drying temperature is room temperature ~ 60 ° C, preferably 40 ° C; and the drying time is 1 ~ 48 hours, preferably 1 ~ 24 hours.

The crystal form I has the following beneficial effects:

(1) The crystal form I is left for one month in a room temperature dryer, an open room temperature, a room temperature-97% RH, a room temperature-75% RH or a room temperature-44% RH, and the crystal form remains unchanged;

(2) The quality change of the crystal form I within a humidity variation range of 20 to 80% RH is only about 0.8%, which is not easy to absorb moisture;

(3) The crystalline form I is the most stable crystalline form in an aqueous system, so it has better application value in wet granulation or suspension formulation.

(4) After being left for 6 months, the preparation prepared with the crystal form I as raw material has no change in the crystal form and dissolution, indicating that it is suitable for the application of the preparation product.

The above properties of the crystalline Form I indicate that the crystalline Form I of the present invention has good stability and low hygroscopicity, and can better resist the content caused by factors such as time and humidity during the manufacturing, storage, and transportation of the drug. Unevenness and reduced purity reduce the risk of curative effect reduction and safety risks caused by changes in the active substance crystal form, unstable content and increased impurity content; and the crystalline form I of the present invention is the most stable crystalline form in an aqueous system, It is more suitable for the solid granulation wet granulation process or made into a suspension, has good formulation processing suitability, good production reproducibility, and is conducive to later storage and transportation.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The crystalline form IV of 3-azetidinecarboxylic acid (hereinafter referred to as "crystalline form IV") and a preparation method thereof, the crystalline form IV is an anhydrous substance.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form IV at a diffraction angle 2θ of 4.8 ± 0.2 °, 9.0 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 ° and There are characteristic peaks at 17.7 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form IV has a diffraction angle 2θ of 4.8 ± 0.2 °, 9.0 ± 0.2 °, 9.8 ± 0.2 °, 12.4 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± There are characteristic peaks at 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, and 19.8 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form IV has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form IV is shown in FIG. 6.

The crystal form IV also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form IV is shown in FIG. 10.

The crystalline form IV is prepared by any one of the following methods: (1) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidinecarboxylic acid forms a suspension in the following organic solvent system, stirs and crystallizes, and separates the precipitated crystals to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IV, wherein the organic solvent is selected From C ₂ ~ C ₃ alcohol, acetone, C ₄ ~ C ₅ ester, tetrahydrofuran, 1,4-dioxane, acetonitrile and mixtures thereof; preferably, the organic solvent is selected from acetone, ethyl acetate, acetic acid Isopropyl ester, 1,4-dioxane, acetonitrile, acetone in ethanol (50% by volume of acetone), tetrahydrofuran in ethanol (50% by volume of tetrahydrofuran), and acetonitrile in ethanol (acetonitrile) 50% by volume), more preferably acetone, ethyl acetate, isopropyl acetate, 1,4-dioxane, and acetonitrile; preferably, the organic solvent is dried, and the volume of water in the organic solvent is Content is less than 0.001%; preferably, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl The amount of the alkyl} -3-azetidinecarboxylic acid is 1.1 to 50 times, more preferably 1.5 to 10 times its solubility in the solvent system at the operating temperature; preferably, the operating temperature is room temperature Preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3-14 days, more preferably 3-7 days; (2 ) Under a certain temperature, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl Butidine carboxylic acid was formed into a solution in an organic solvent, cooled and stirred for crystallization, and the precipitated crystals were separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline form IV of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, wherein the organic solvent is selected from the group consisting of C ₁ to C ₄ alcohols, C ₃ to C ₄ ketones, C ₄ ~ C ₅ ester, 1,4-dioxane, acetonitrile, toluene and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, 2-butanol, N-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, 1,4-dioxane, toluene and ethanol in acetonitrile (25% ethanol by volume), more preferably methanol, ethanol, Isopropanol, Butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, 1,4-dioxane, toluene; preferably, the organic solvent is dried, and the volume content of water in the organic solvent is less than 0.001% ; Preferably, in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} The amount of -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the organic solvent at a certain temperature, more preferably 0.5 to 1 times; preferably, the certain temperature is 40 ° C to 80 ° C. , More preferably 50 ° C to 80 ° C; preferably, the temperature after cooling is room temperature; preferably, the crystallization time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (3) To 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in A slightly soluble or insoluble solvent is added to the solution formed in the soluble solvent, and the crystals are stirred and crystallized. The precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IV, wherein the soluble solvent is selected from the group consisting of trifluoroethanol, tetrahydrofuran, 1,4-bis Oxycyclo, dimethylarsine or mixtures thereof; The slightly soluble or insoluble solvent is selected from the group consisting of C ₃ ~ C ₄ alcohol, C ₄ ~ C ₅ ester, isopropyl ether, n-heptane or a mixture thereof; preferably, the soluble solvent is selected from trifluoroethanol, tetrahydrofuran 1,4-dioxane or dimethylarsin; preferably, the slightly soluble or insoluble solvent is selected from the group consisting of n-propanol, n-butanol, 2-butanol, ethyl acetate, isopropyl acetate, Isopropyl ether or n-heptane; preferably, the solvents are dried, and the volume content of water in the organic solvent is less than 0.001%; preferably, the volume ratio of the slightly soluble or insoluble solvent to the soluble solvent is 1: 1 to 50: 1, more preferably 1: 1 to 10: 1; preferably, in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl)- The amount of 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the soluble solvent at the operating temperature; more preferably 0.5 ~ 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization The time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (4) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -Benzyl} -3-azetidinecarboxylic acid solution in an organic solvent is evaporated and crystallized, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylbenzene) Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid crystalline form IV; wherein the organic solvent is selected from the group consisting of C ₁ to C ₄ alcohols, C ₄ ~ C ₅ ester, methyl ethyl ketone, tetrahydrofuran, dimethylarsine, or a mixture thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, 2-butanol, n-butanol, butane Ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran or dimethylarsin; preferably, the organic solvent is dried and the volume content of water in the organic solvent is less than 0.001%; preferably, 1- {2- The amount of fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is its The solubility in the solvent system is 0.1 to 1 times, more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, More preferably, it is room temperature; preferably, the crystallization time is 1 to 7 days, more preferably 3 to 7 days; in the above-mentioned preparation method of (1) to (4) crystal form IV, the dry Temperature is room temperature ~ 60 ℃, preferably 40 ℃; the drying time is 1 to 48 hours, preferably 1 to 24 hours.

The crystal form IV has the following beneficial effects: (1) The crystal form IV is at room temperature dryer, room temperature open, room temperature-97% RH, room temperature-75% RH or room temperature-44% RH The crystal form remains unchanged after being left for 1 month; (2) the quality change of the crystal form IV within the range of 20 ~ 80% RH humidity is about 1.6%; (3) the crystal form IV is the most under the condition of pure organic solvent Stable crystalline form; (4) The crystalline form IV is rod-shaped particles with large particles and good fluidity; (5) The crystalline form and dissolution of the preparation prepared with the crystalline form IV as a raw material after 6 months of standing The degree has not changed, indicating that it is suitable for the application of preparation products.

The above properties of the crystalline form IV indicate that the crystalline form of the present invention has good crystalline form stability and low hygroscopicity, and can better resist the content caused by factors such as time and humidity during the manufacturing, storage, and transportation of the drug. Unevenness and decreased purity To reduce the risk of curative effect and safety risks caused by changes in the crystal form of the active substance, unstable content and increased impurity content; and the crystal form IV of the present invention is the most stable crystal form in pure organic solvents and has good preparation processing Suitability, good production reproducibility, and favorable for later storage and transportation; the particles of the crystal form VI of the present invention have good morphology and good fluidity, which is conducive to accurate quantification and pouring in the preparation of the preparation, and has good production reproducibility, Has good formulation processing suitability.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The crystal form XII of 3-azetidincarboxylic acid (hereinafter referred to as "crystal form XII") and a preparation method thereof, the crystal form XII is an anhydrous substance.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form XII is at diffraction angles 2θ of 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 °, and 19.3 ± 0.2 ° There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the crystal form XII has a diffraction angle 2θ of 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 °, 19.3 ± 0.2 °, 21.8 ± There are characteristic peaks at 0.2 °, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 °, and 25.7 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form XII has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form XII is shown in FIG. 11.

The crystal form XII also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form XII is shown in FIG. 15.

The crystal form XII is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl Group} -3-azetidinecarboxylic acid in suspension in anhydrous methanol, crystallized by stirring, the precipitated crystals were separated and dried to obtain the 1- {2-fluoro-4- [5- (4-isobutyl) Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form XII; preferably, 1- {2-fluoro-4- [ The amount of 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is the same as that in anhydrous methanol at the operating temperature. The solubility is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the operating temperature is room temperature; Preferably, the crystallization time is 3-14 days, more preferably 3-7 days. In the method for preparing the crystal form XII, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; The drying time is 1 to 48 hours, preferably 1 to 24 hours.

The crystal form XII has the following beneficial effects: (1) The crystal form XII is at room temperature dryer, room temperature open, room temperature-97% RH, room temperature-75% RH or room temperature-44% RH The crystal form remains unchanged after being left for 1 month; (2) the quality change of the crystal form XII is only about 1.3% in the humidity variation range of 20 to 80% RH; (3) the crystal form XII has a better quality in water Stability; (4) The crystalline form and dissolution of the preparation prepared with the crystal form XII as raw materials after 6 months have not changed, indicating that it is suitable for the application of the preparation product.

The above properties of the crystalline form XII indicate that the crystalline form XII of the present invention has good stability and low hygroscopicity, and can better resist the content caused by factors such as time and humidity during the manufacturing, storage, and transportation of the drug. Problems such as unevenness and decreased purity reduce the risk of curative effect reduction and safety risks caused by changes in the active substance crystal form, unstable content, and increased impurity content; and the crystal form XII of the present invention has certain stability in water and is more suitable The wet granulation process or suspension preparation of solid preparations has good formulation processing suitability, good production reproducibility, and is conducive to later storage and transportation.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Form II of 3-azetidincarboxylic acid (hereinafter referred to as "form II") and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at the diffraction angle 2θ is 5.3 ± 0.2 °, 12.8 ± 0.2 °, 14.7 ± 0.2 °, 16.9 ± 0.2 °, 19.1 ± 0.2 ° and There are characteristic peaks at 19.5 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form II has a diffraction angle 2θ of 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.1 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 14.7 ± There are characteristic peaks at 0.2 °, 15.6 ± 0.2 °, 16.9 ± 0.2 °, 18.5 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, and 21.7 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form II has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form II is shown in FIG. 16.

The crystal form II also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form II is shown in FIG. 17.

The crystal form II is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl The crystalline form I of the 3-yl} -3-azetidincarboxylic acid is heated to completely decrystallize water, and then naturally cooled to room temperature to crystallize, to obtain 1- {2-fluoro-4- [5- (4-isobutylbenzene) Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidine carboxylic acid Form II; preferably, the temperature increasing method is TGA, DSC, hot stage or An oven; preferably, the temperature to which the temperature is raised is 100 ° C to 150 ° C; preferably, the crystallization time is 0.5 to 24 hours.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline III (hereinafter referred to as "crystal III") of 3-azetidincarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form III at the diffraction angle 2θ is 4.1 ± 0.2 °, 4.9 ± 0.2 °, 8.2 ± 0.2 °, 8.8 ± 0.2 °, 11.3 ± 0.2 ° and There are characteristic peaks at 12.3 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form III is 4.1 ± 0.2 °, 4.9 ± 0.2 °, 8.2 ± 0.2 °, 8.8 ± 0.2 °, 9.8 ± 0.2 °, 11.3 ± There are characteristic peaks at 0.2 °, 12.3 ± 0.2 °, 19.8 ± 0.2 °, 22.0 ± 0.2 °, and 24.8 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form III has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Without limitation, in a specific embodiment of the invention, all The X-ray powder diffraction pattern of the crystal form III is shown in FIG. 18.

The crystal form III also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form III is shown in FIG. 19.

The crystal form III is prepared by any one of the following methods: (1) to 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole 3--3-yl] -benzyl} -3-azetidinecarboxylic acid in a solution of trifluoroethanol was added with an anti-solvent, and the crystals were stirred and crystallized, and the precipitated crystals were separated without drying to obtain 1- {2- Form III of fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, wherein The anti-solvent is selected from water, C ₃ ~ C ₄ ketone, C ₄ ester, C ₅ -C ₆ ether, acetonitrile, or a mixture thereof; preferably, the anti-solvent is selected from water, acetone, ethyl acetate, isopropyl Ether, methyl tertiary butyl ether, acetonitrile; preferably, the volume ratio of the anti-solvent to trifluoroethanol is 1: 1 to 50: 1, more preferably 1: 1 to 10: 1; preferably In the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl The amount of butidinecarboxylic acid is 0.1 to 1 times its solubility in trifluoroethanol at operating temperature; more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the The crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization The time is 0.5 to 72 hours, more preferably 0.5 to 10 hours; (2) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidinecarboxylic acid in trifluoroethanol solution is evaporated and crystallized, and the precipitated crystals are separated without drying to obtain 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form III; preferably, 1- {2 The amount of -fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is at the operating temperature Its solubility in trifluoroethanol is 0.1 to 1 times, more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is room temperature; preferably The crystallization time is 1 to 7 days, and more preferably 3 to 7 days.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form V (hereinafter referred to as "crystal form V") of 3-azetidincarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form V at the diffraction angle 2θ is 6.2 ± 0.2 °, 11.4 ± 0.2 °, 13.5 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 ° and There are characteristic peaks at 18.9 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form V at the diffraction angle 2θ is 6.2 ± 0.2 °, 8.0 ± 0.2 °, 11.4 ± 0.2 °, 12.6 ± 0.2 °, 13.5 ± 0.2 °, 16.2 ± There are characteristic peaks at 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 °, 18.9 ± 0.2 °, 20.4 ± 0.2 °, and 22.6 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form V has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 20.

The crystal form V also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form V is shown in FIG. 21.

The crystal form V is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl Group} -3-azetidinecarboxylic acid forms a suspension in n-butanol, and is crystallized by stirring, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form V; preferably, 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of 1.1 to 50 times the solubility, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; Preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3-14 days, more preferably 3-7 days; In the preparation method, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; and the drying time is from 1 to 48 hours, preferably from 1 to 24 hours.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form VI (hereinafter referred to as "crystal form VI") of 3-azetidincarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form VI at diffraction angles 2θ of 6.8 ± 0.2 °, 7.2 ± 0.2 °, 8.9 ± 0.2 °, 17.2 ± 0.2 °, and 17.7 ± 0.2 ° There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the crystal form VI has a diffraction angle 2θ of 5.7 ± 0.2 °, 6.2 ± 0.2 °, 6.8 ± 0.2 °, 7.2 ± 0.2 °, 8.9 ± 0.2 °, 13.6 ± There are characteristic peaks at 0.2 °, 14.5 ± 0.2 °, 17.2 ± 0.2 °, 17.7 ± 0.2 °, 18.4 ± 0.2 °, and 19.4 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form VI has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form VI is shown in FIG. 22.

The crystal form VI is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl Group} -3-azetidinecarboxylic acid in suspension in ethanol, crystallized by stirring, the precipitated crystals were separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid crystalline form VI; preferably, 1- {2-fluoro-4- [5- ( The amount of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1.1 to its solubility in ethanol at the operating temperature. 50 times, more preferably 1.5 to 10 times; Preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3-14 days, more Preferably, it is 3-7 days; in the above method for preparing Form VI, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; the drying time is from 1 to 48 hours, preferably from 1 to 24 hours .

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form VII of 3-azetidinecarboxylic acid (hereinafter referred to as "crystal form VII") and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form VII at a diffraction angle 2θ of 5.6 ± 0.2 °, 8.4 ± 0.2 °, 11.3 ± 0.2 °, 19.9 ± 0.2 °, 22.8 ± 0.2 ° and There are characteristic peaks at 25.8 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form VII has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form VII is shown in FIG. 23.

The crystal form VII also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form VII is shown in FIG. 24.

The crystalline form VII is prepared by the following method: forming 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl A solution of the methyl} -3-azetidinecarboxylic acid in dimethylarsine, the reaction bottle of the solution was opened in a closed atmosphere filled with water, and the water vapor was diffused into the dimethylarsine solution to crystallize. The precipitated crystals were separated without drying to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} Crystalline form VII of -3-azetidincarboxylic acid; preferably, the volume ratio of water to dimethylarsine is 1: 1 to 50: 1, more preferably 1: 1 to 10: 1; 1,1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid The amount used is 0.1 to 1 times its solubility in dimethylarsine at operating temperature; more preferably 0.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature The temperature is from room temperature to 60 ° C, more preferably room temperature; preferably, the crystallization time is 3-14 days, and more preferably 7-14 days.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form VIII (hereinafter referred to as "crystal form VIII") of 3-azetidinecarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form VIII at the diffraction angle 2θ is 3.5 ± 0.2 °, 7.2 ± 0.2 °, 14.5 ± 0.2 °, 17.7 ± 0.2 °, 18.5 ± 0.2 ° There are characteristic peaks at 19.5 ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of the crystal form VIII has a diffraction angle 2θ of 3.5 ± 0.2 °, 7.2 ± 0.2 °, 9.8 ± 0.2 °, 12.7 ± 0.2 °, 14.5 ± 0.2 °, 16.8 ± There are characteristic peaks at 0.2 °, 17.2 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, 18.5 ± 0.2 ° and 19.5 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form VIII has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Without limitation, in a specific embodiment of the invention, all The X-ray powder diffraction pattern of the crystal form VIII is shown in FIG. 25.

The crystal form VIII also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form VIII is shown in FIG. 26.

The crystal form VIII is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl The crystalline form VI of the methyl} -3-azetidinecarboxylic acid forms a suspension in ethanol, and is crystallized by stirring, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-iso Butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, Form VIII; preferably, the amount of Form VI is at the operating temperature Its solubility in ethanol is 1.1 to 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably It is room temperature; preferably, the crystallization time is 3-14 days, more preferably 3-7 days; in the method for preparing the crystal form VIII, the drying temperature is room temperature to 60 ° C, preferably 40 ° C; the drying time is 1 to 48 hours, preferably 1 to 24 hours.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form IX (hereinafter referred to as "crystal form IX") of 3-azetidincarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form IX at the diffraction angle 2θ is 6.2 ± 0.2 °, 7.0 ± 0.2 °, 12.5 ± 0.2 °, 17.1 ± 0.2 °, 17.5 ± 0.2 ° and Characteristic peak at 17.9 ± 0.2 °

Preferably, the X-ray powder diffraction pattern of the crystal form IX has a diffraction angle 2θ of 4.8 ± 0.2 °, 6.2 ± 0.2 °, 7.0 ± 0.2 °, 8.2 ± 0.2 °, 9.7 ± 0.2 °, 11.5 ± There are characteristic peaks at 0.2 °, 12.5 ± 0.2 °, 13.4 ± 0.2 °, 14.3 ± 0.2 °, 17.1 ± 0.2 °, 17.5 ± 0.2 °, and 17.9 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form IX has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position: 24.2 ± 0.2 ° 11.3.

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form IX is shown in FIG. 27.

The crystal form IX also has at least one of the following characteristics: Non-limitingly, in a specific embodiment of the present invention, the FT-IR chart of the crystal form IX is shown in FIG. 28.

The crystal form IX is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl }}-3-azetidinecarboxylic acid forms a suspension in isopropanol, crystallizes by stirring, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IX; preferably, 1- {2-fluoro-4- [5 The amount of-(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is the same as that in isopropanol at the operating temperature. 1.1 to 50 times the solubility, more preferably 1.5 to 10 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably room temperature; Preferably, the crystallization time is 3-14 days, more preferably 3-7 days. In the above-mentioned preparation method of the crystal form IX, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; The drying time is 1 to 48 hours, preferably 1 to 24 hours.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Form X of 3-azetidincarboxylic acid (hereinafter referred to as "form X") and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form X is at diffraction angles 2θ of 3.1 ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 17.7 ± 0.2 °, and 18.1 ± 0.2 ° There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the crystal form X has a diffraction angle 2θ of 3.1 ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 14.5 ± 0.2 °, 16.5 ± 0.2 °, 17.7 ± There are characteristic peaks at 0.2 °, 18.1 ± 0.2 °, 18.4 ± 0.2 °, 19.2 ± 0.2 °, and 22.2 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form X has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form X is shown in FIG. 29.

The crystal form X also has at least one of the following characteristics: without limitation, in a specific embodiment of the present invention, the crystal form X The FT-IR chart is shown in Figure 30.

The crystal form X is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl A solution of the group} -3-azetidinecarboxylic acid in 1,4-dioxane is evaporated and crystallized, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form X; preferably, 1- {2-fluoro-4 The amount of-[5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is at 1, The solubility in 4-dioxane is 0.1 to 1 times, more preferably 9.5 to 1 times; preferably, the operating temperature is room temperature; preferably, the crystallization temperature is from room temperature to 60 ° C. , More preferably 60 ° C; preferably, the crystallization time is 1 to 7 days, more preferably 3 to 7 days; in the above method for preparing the crystal form X, the drying temperature is room temperature to 60 ° C, It is preferably 40 ° C; the drying time is 1 to 48 hours, and preferably 1 to 24 hours.

According to the purpose of the present invention, the present invention provides 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- Crystalline form XI (hereinafter referred to as "crystal form XI") of 3-azetidincarboxylic acid and a method for preparing the same.

Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form XI at diffraction angles 2θ of 8.9 ± 0.2 °, 15.0 ± 0.2 °, 15.7 ± 0.2 °, 18.2 ± 0.2 °, and 18.7 ± 0.2 ° There are characteristic peaks.

Preferably, the X-ray powder diffraction pattern of the crystal form XI at the diffraction angle 2θ is 8.9 ± 0.2 °, 9.6 ± 0.2 °, 15.0 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.0 ± 0.2 °, There are characteristic peaks at 17.3 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, and 18.7 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the crystal form XI has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position:

Non-limitingly, in a specific embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form XI is shown in FIG. 31.

The crystal form XI also has at least one of the following characteristics: non-limitingly, in a specific embodiment of the present invention, the crystal form XI The FT-IR chart is shown in Figure 32.

The crystal form XI is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl Group} -3-azetidinecarboxylic acid forms a suspension in toluene, and is crystallized by stirring, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid crystalline form XI; preferably, 1- {2-fluoro-4- [5- ( The amount of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1.1 ~ its solubility in toluene at the operating temperature 50 times, more preferably 1.5 to 10 times; preferably, the operating temperature is 60 ° C; preferably, the crystallization temperature is from room temperature to 60 ° C, more preferably 60 ° C; preferably, all The crystallization time is 3-14 days, more preferably 3-7 days. In the above method for preparing the crystal form XI, the drying temperature is from room temperature to 60 ° C, preferably 40 ° C; the drying time is 1 ~ 48 hours, preferably 1 to 24 hours.

According to the present invention, Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, and Form XI In the above preparation method, the stirring may be performed by a conventional method in the art, such as magnetic stirring, mechanical stirring, and the like. The stirring rate is 50 to 1800 rpm, preferably 300 to 900 rpm.

According to the present invention, Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, and Form XI In the above preparation method, the precipitated crystals are separated by conventional methods in the art. Isolate, wash and dry. The separation is performed by conventional methods in the art such as filtration, centrifugation, etc. The specific operation of filtration is: placing the sample to be separated on a filter paper, and filtering under reduced pressure; the specific operation of centrifugation is: placing the sample to be separated Centrifuge the tube, and then rotate it at high speed until all the solids sink to the bottom of the centrifuge tube. The centrifugation rate is, for example, 6000 rpm. The washing solvent is preferably the same as the solvent used in the method for preparing a crystal form, and the amount of the washing solvent is 2-10 times that of the crystallization solvent. The drying is performed by a conventional method in the art such as natural drying, blast drying, or reduced pressure drying; the drying equipment is a fume hood, a blast oven, or a vacuum oven; drying is performed under reduced pressure or not reduced pressure, and the pressure is preferably less than 0.09Mpa; drying temperature is about room temperature to 60 ° C; drying time is 1 to 48 hours, preferably 1 to 24 hours.

In the present invention, the "room temperature" means about 10-30 ° C.

In the present invention, "crystalline", "crystalline form" or "amorphous" refers to the one confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art can understand that the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern usually changes depending on the conditions of the instrument. It is important to point out that the relative intensity of the X-ray diffraction pattern may also change with changes in experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less. The error of these angles should also be taken into account, and usually an error of ± 0.2 ° is allowed. In addition, due to the influence of experimental factors such as sample height, the overall shift of the peak angle will be caused, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that any crystal form having the same or similar characteristic peaks as the characteristic peaks of the spectrum of the present invention belongs to the scope of the present invention. All The "single crystal form" refers to a single crystal form as determined by X-ray powder diffraction.

In the present invention, Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI are Pure, single, and essentially free of any other crystalline or amorphous form. In the present invention, "substantially absent" when used to refer to a new crystal form means that other crystal forms or amorphous substances contained in this new crystal form are less than 20% by weight, and more than 10% by weight, This means in particular less than 5% by weight, in particular less than 1% by weight.

The starting material of the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl Butidinecarboxylic acid can be prepared by referring to the preparation method of patent document CN103450171A.

Further, the present invention provides a pharmaceutical composition comprising a therapeutic and / or prophylactically effective amount of one or more of the crystalline and amorphous forms of the present invention or the crystalline and amorphous forms prepared by the method of the present invention, And at least one pharmaceutically acceptable carrier. Among them, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid The crystalline and amorphous forms include Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X , Form XI and Amorphous. In addition, the pharmaceutical composition may further include 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} Other pharmaceutically acceptable crystalline or amorphous forms of -3-azetidincarboxylic acid, or 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- Oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-ox Diazol-3-yl] -benzyl} -3-azetidinecarboxylic acid other salts are pharmaceutically acceptable crystalline or amorphous. Pharmaceutical compositions described herein It can be a pharmaceutical preparation itself, or it can be formulated into a pharmaceutical preparation or a combined pharmaceutical preparation with other excipients or drugs.

The above pharmaceutical composition can be made into a certain dosage form, preferably oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, transdermal administration, buccal administration, nasal administration Dosage forms such as medicines include, but are not limited to, solid dosage forms, liquid dosage forms, semi-liquid dosage forms, aerosols, or suppositories. For example, dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions; dosage forms suitable for parenteral administration include aqueous or non-aqueous solutions or Emulsions; formulations suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers; formulations suitable for transdermal administration include ointments and creams; formulations suitable for nasal administration include aerosols and sprays. According to need, the above dosage forms may be suitable for rapid release, delayed release, or modified release of the active ingredient.

The pharmaceutically acceptable carriers according to the present invention include solid carriers, including, but not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, and tricalcium phosphate. , Mannitol, sorbitol, sugar, etc .; binders, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, etc .; disintegrants , Such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, etc .; lubricants, such as stearic acid, magnesium stearate, stearin Zinc acid, sodium benzoate, sodium acetate, etc .; glidants, such as colloidal silica, etc .; complex-forming agents, such as various grades of cyclodextrin and resins; release rate control agents, such as hydroxypropyl cellulose, hydroxymethyl Cellulose, hydroxypropyl methyl cellulose, ethyl cellulose Vitamins, methyl cellulose, methyl methacrylate, wax, etc. The pharmaceutically acceptable carriers in the present invention also include liquid carriers, including, but not limited to, solvents such as aqueous, oily or alcoholic solutions such as sterile water, physiological saline solution, glucose solution, mannitol solution, vegetable oil, cod liver oil, Ethanol, propanol, glycerin, etc. In addition, carriers such as polyethylene glycol and polypropylene glycol can also be used. Other pharmaceutically acceptable carriers can be selected according to different dosage forms, including, but not limited to, film-forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, penetrants, buffers Wait. Each carrier must be acceptable, compatible with the other ingredients in the formulation and not harmful to the patient.

The pharmaceutical composition can be prepared using methods known to those skilled in the art. When preparing a pharmaceutical composition, Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Crystal Form X, Form XI, amorphous or a combination thereof is mixed with one or more pharmaceutically acceptable carriers, optionally with one or more other pharmaceutically active ingredients. Solid preparations can be prepared by mixing, granulation and other processes, and liquid or semi-liquid dosage forms can be prepared by mixing, dissolving, dispersing, emulsifying and other processes.

Further, the present invention provides the use of the crystalline form and amorphous form of the present invention or the crystalline form and amorphous form obtained by the preparation method of the present invention in the manufacture of a medicament for treating and / or preventing a disease or condition mediated by the S1P1 receptor. . Wherein the crystalline and amorphous forms include 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- 3-Acetidinecarboxylic acid Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Amorphous or combination thereof. The disease or condition mediated by the S1P1 receptor is selected from rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, autoimmune disease, chronic inflammatory disease, asthma, inflammatory neuropathy, arthritis, transplantation, Segmental ileitis, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain disorders, acute viral disease, inflammatory bowel disease, insulin and Non-insulin-dependent diabetes and other related immune diseases; preferably, the disease or condition is selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

Further, the present invention provides a method of treating and / or preventing a disease or condition mediated by the S1P1 receptor, said method comprising administering to a subject in need thereof a therapeutic and / or preventive effective amount of a crystalline form of the present invention and an A shape or a combination thereof or a pharmaceutical composition thereof, wherein the crystalline and amorphous forms include 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidinecarboxylic acid Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Amorphous, or a combination thereof. The disease or condition mediated by the S1P1 receptor is selected from rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, autoimmune disease, chronic inflammatory disease, asthma, inflammatory neuropathy, arthritis, transplantation, Segmental ileitis, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain disorders, acute viral disease, inflammatory bowel disease, insulin and Non-insulin-dependent diabetes and other related immune diseases; preferably, the disease or condition is selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis. The subject This includes, but is not limited to, mammals. The crystalline and amorphous forms provided by the present invention or a combination thereof or a pharmaceutical composition thereof can be co-administered with other therapies or therapeutic agents. In addition, the dosage of the compound or pharmaceutical composition required for the effect of treatment, prevention or alleviation usually depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be treated The doctor decides according to the specific situation.

Fig. 1 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form I of butidinecarboxylic acid.

FIG. 2 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl PLM pattern of crystalline form I of butidinecarboxylic acid.

Fig. 3 is the present invention 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl TGA / DSC pattern of Form I of butidinecarboxylic acid.

FIG. 4 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl DVS isotherm adsorption diagram of crystalline form I of butidinecarboxylic acid.

Fig. 5 is the present invention 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR pattern of crystalline form I of butidinecarboxylic acid.

Fig. 6 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form IV of butidinecarboxylic acid.

FIG. 7 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl PLM pattern of crystalline form IV of butidinecarboxylic acid.

Fig. 8 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl TGA / DSC pattern of Form IV of butidinecarboxylic acid.

FIG. 9 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl DVS isotherm adsorption diagram of crystalline form IV of butidinecarboxylic acid.

FIG. 10 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of form IV of butidinecarboxylic acid.

FIG. 11 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of crystalline form XII of butidinecarboxylic acid.

Fig. 12 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl PLM pattern of crystalline form XII of butidinecarboxylic acid.

Fig. 13 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl TGA / DSC pattern of crystalline form XII of butidinecarboxylic acid.

FIG. 14 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl DVS isotherm adsorption profile of butadicarboxylic acid in crystalline form XII.

Fig. 15 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR pattern of crystalline form XII of butidinecarboxylic acid.

FIG. 16 shows the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form II of butidinecarboxylic acid.

Fig. 17 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR pattern of Form II of butidinecarboxylic acid.

FIG. 18 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form III of butidinecarboxylic acid.

FIG. 19 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of Form III of butidinecarboxylic acid.

FIG. 20 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form V of butidinecarboxylic acid.

Fig. 21 is 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-LR pattern of Form V of butidinecarboxylic acid.

Fig. 22 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of crystalline form VI of butidinecarboxylic acid.

Fig. 23 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form VII of butidinecarboxylic acid.

Fig. 24 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of butinecarboxylic acid, Form VII.

Fig. 25 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form VIII of butidinecarboxylic acid.

Fig. 26 is 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of butidinecarboxylic acid, Form VIII.

FIG. 27 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of butidinecarboxylic acid, Form IX.

Fig. 28 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of butidinecarboxylic acid, Form IX.

Fig. 29 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form X of butidinecarboxylic acid.

Fig. 30 is 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR pattern of Form X of butidinecarboxylic acid.

FIG. 31 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl XRPD pattern of Form XI of butidinecarboxylic acid.

FIG. 32 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl FT-IR spectrum of butidinecarboxylic acid, Form XI.

Fig. 33 is 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl Amorphous XRPD pattern of butidinecarboxylic acid.

Fig. 34 is the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl Amorphous FT-IR spectrum of butidinecarboxylic acid.

The following examples will help to further understand the present invention, but are not intended to limit the present invention.

Testing instruments and methods: X-Ray Powder Diffraction (XPRD): The instrument used is Bruker D8 Advance diffractometer, using Ka X-rays with a copper target wavelength of 1.54nm, under the operating conditions of 40kV and 40mA, θ-2θ goniometer, Mo Monochromator, Lynxeye detector. The instrument was calibrated with emery before use. The acquisition software is Diffrac Plus XRD Commander. The sample is tested at room temperature. The sample to be tested is placed on a non-reflective plate. The detailed detection conditions are as follows, angle range: 3-40 ° 2θ, step size: 0.02 ° 2θ, speed: 0.2 seconds / step.

Differential Thermal Analysis (DSC): The data is taken from TAInstrumentsQ200MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually takes 1-10 mg sample is placed in an aluminum pan, a heating rate of 10 ℃ / min at 40mL / min under the protection of dry N ₂ The sample was raised from room temperature to 250 deg.] C.

Thermogravimetric analysis (TGA): The data is taken from TAInstrumentsQ500TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually take a sample of 1-15 mg in a platinum crucible and use segmented high-resolution detection to raise the sample from room temperature to 300 ° C at a heating rate of 10 ° C / min under the protection of dry mL ₂ of 40mL / min. .

Isothermal Adsorption Curve (DVS): The data is taken from TA Instruments Q5000 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, a 1-10 mg sample is placed in a platinum crucible, and the TA software records the weight change of the sample during the relative humidity change from 0% to 90% to 0%. Depending on the sample, different adsorption and desorption steps are also applied to the sample.

H NMR data ⁽¹ HNMR) collected from a Bruker Avance II DMX 400MHZ NMR spectrometer. A 1-5 mg sample was weighed, dissolved with 0.5 mL of deuterated chloroform (CDCl ₃ ), and prepared into a 2 mg / mL-10 mg / mL solution.

Fourier Infrared Spectroscopy (FT-IR) data was collected from Bruker Tensor 27. Instrument control software and data analysis software are OPUS. Generally, ATR equipment is used. In the range of 600-4000cm ^-1 , infrared absorption spectra are collected. The scanning time of the sample and the blank background is 32 seconds, and the instrument resolution is 4cm ^-1 .

Various reagents used in the examples are commercially available unless otherwise specified.

The ultrasonic operation in the embodiment can promote the dissolution of the sample. The equipment is an ultrasonic cleaner, which is performed at a power of 40 kHz for 15 minutes.

Preparation Example 1

Compound 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid may It is prepared by referring to the preparation method of Example 2 of Patent Document CN103450171A. Specifically, at room temperature, 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzaldehyde (0.90 g, 2.78 mmol ), 3-azetidinecarboxylic acid (0.28g, 2.78mmol) and acetic acid (1mL) in methanol-tetrahydrofuran (20mL / 20mL) was stirred for 2 hours, and sodium cyanoborohydride (1.03g, 16.35mmol) in methanol was added. After the solution (60 mL) was stirred at room temperature for 16 hours, filtered, and the filter cake was washed with methanol (10 mL) and dried to give a white solid product 1- {2-fluoro-4- [5- (4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid (Compound 2) (0.20 g). 1H-NMR (400MHz, CD3OD) δ: 8.13 (d, J = 8.4Hz, 2H), 8.05 (m, 1H), 7.97 (m, 1H), 7.68 (t, J = 8.0Hz, 7.6Hz, 1H) , 7.42 (d, J = 8.4Hz, 2H), 4.40 (s, 2H), 4.15 (m, 4H), 3.41 (m, 1H), 2.61 (d, J = 7.2Hz, 2H), 1.95 (m, 1H), 0.94 (d, J = 7.2Hz, 6H).

The X-ray powder diffraction pattern is shown in Fig. 33 and is amorphous.

The FT-IR spectrum is shown in Figure 34.

Example 1

At room temperature, 130.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. Base} -3-azetidinecarboxylic acid and 13.0 mL of acetone in water (67% by volume of water), sonicated for 15 minutes to obtain a white suspension Liquid (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl in this suspension The amount of butidinecarboxylic acid used was 50 times its solubility in an acetone aqueous solution at room temperature), crystallized by stirring at room temperature for 7 days, filtered, and the resulting solid was dried under vacuum at 40 ° C for 48 hours to obtain the present invention 1- { Form I of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 120.1 mg; the yield was 95%.

The X-ray powder diffraction pattern is shown in Figure 1 and is in Form I.

The PLM map is shown in Figure 2. Display: Fine crystals.

DSC and TGA spectra are shown in Figure 3. It shows that Form I has a broad endothermic peak (solvent peak) at 3 ~ 115 ℃, and the melting point of the sample after dehydration is 179 ℃; Form I loses about 2.2% of the weight loss in steps before 50 ~ 125 ℃, and hemihydrate theory The value (2.2%) agrees, and the decomposition temperature is 182 ° C.

The DVS map is shown in Figure 4. Display: The weight change from 20% RH to 80% RH is 0.8%.

The FT-IR spectrum is shown in Figure 5.

The above test results show that the crystal form I is a hemihydrate and is not easy to absorb moisture.

Example 2

At room temperature, 0.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 18.0 mL of water, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in 50 times its solubility in water at room temperature), and crystallized by stirring at 60 ° C for 7 days, Filtration and vacuum drying of the obtained solid for 24 hours at room temperature gave the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3- [Formula] -benzyl} -3-azetidininecarboxylic acid Form I. The yield was 0.7 mg; the yield was 78%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 3

At room temperature, 15.4 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 2.5 mL of ethanol aqueous solution (50% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl] -3-azetidinecarboxylic acid is used at 10 times its solubility in aqueous ethanol at room temperature) , Crystallize by stirring at room temperature for 3 days, filter, and dry the obtained solid under vacuum at 40 ° C. for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form I of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 13.1 mg; the yield was 85%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 4

At room temperature, 1.3 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 3.0 mL of methanol in water (67% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in an amount of 1.1 times its solubility in aqueous methanol at room temperature) , Crystallize by stirring at room temperature for 3 days, filter, and dry the obtained solid under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, 2,4-oxadiazole-3- [Formula] -benzyl} -3-azetidininecarboxylic acid Form I. The yield was 0.1 mg; the yield was 0.8%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 5

At room temperature, 0.6 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Yl} -3-azetidincarboxylic acid and 1.3 mL of n-propanol aqueous solution (water content 1.0%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in aqueous n-propanol at room temperature 1.5 times), crystallize by stirring at room temperature for 7 days, centrifuge, and dry the obtained solid under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 0.3 mg; the yield was 50%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 6

At room temperature, 3.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Group} -3-azetidinecarboxylic acid and 1.0 mL of isopropanol aqueous solution (5.0% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in aqueous isopropanol at room temperature 10 times), crystallized by stirring at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 2.7 mg; the yield was 87%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 7

At room temperature, 3.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Base} -3-azetidinecarboxylic acid and 1.6 mL of n-butanol aqueous solution (0.01% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in aqueous n-butanol at room temperature 10 times), stirred at 60 ° C for 7 days to crystallize, filtered, and the obtained solid was dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 2.5 mg; the yield was 78%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 8

At room temperature, add 3.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5 mL glass bottle. Based} -3-azetidinecarboxylic acid and 1.5 mL of 2-butanol aqueous solution (water volume content of 0.1%), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in an aqueous 2-butanol solution at room temperature 10 times the solubility), crystallized by stirring at room temperature for 14 days, centrifuged, and the obtained solid was dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylbenzene) Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form I. The yield was 2.7 mg; the yield was 90%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 9

At room temperature, add 3.0mg 1- {2-fluoro -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 60 mL of methyl tertiary butyl Aqueous ether solution (water content 0.1%), ultrasonication for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- The amount of oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 50 times its solubility in methyl tertiary butyl ether aqueous solution at room temperature), and stirred at room temperature for 14 days Crystallize, centrifuge, and dry the obtained solid at 60 ° C under vacuum for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form I. The yield was 2.7 mg; the yield was 90%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 10

At room temperature, add 2.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 100 mL single-necked flask. Base} -3-azetidinecarboxylic acid and 60 mL of an isopropyl ether aqueous solution (water content 0.01%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in an amount corresponding to its solubility in an isopropyl ether aqueous solution at room temperature 50 times), crystallize by stirring at room temperature for 7 days, filter, and dry the obtained solid under vacuum for 1 hour at room temperature to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 2.0 mg; the yield was 69%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 11

At room temperature, 4.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-Acetidinecarboxylic acid and 2.0 mL Ketone aqueous solution (water content 0.1%), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- The amount of oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 10 times its solubility in the methyl ethyl ketone aqueous solution at room temperature), and it is crystallized by stirring at room temperature for 3 days. The obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] according to the present invention. -Benzyl} -3-azetidininecarboxylic acid, crystalline form I. The yield was 3.3 mg; the yield was 80%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 12

At room temperature, 2.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 5.0 mL of ethyl acetate aqueous solution (water volume content 0.01%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in aqueous ethyl acetate at room temperature 50 times), crystallization after stirring at room temperature for 7 days, centrifugation, and drying the obtained solid under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 2.1 mg; the yield was 84%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 13

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 3.6 mL of a solution of nitromethane (water content 1.0%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl The amount of methyl} -3-azetidinecarboxylic acid is 50 times its solubility in aqueous nitromethane solution at room temperature), stirred at 40 ° C for 7 days to crystallize, filtered, and dried the obtained solid under vacuum at 40 ° C for 24 hours. Hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidine Crystalline form I of pyridinecarboxylic acid. The yield was 1.3 mg; the yield was 72%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 14

At room temperature, 2.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 5.0 mL of dichloromethane aqueous solution (water content 0.1%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in dichloromethane aqueous solution at room temperature 40 times), crystallization after stirring at 40 ° C for 7 days, filtration, and the obtained solid was dried under vacuum at room temperature for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 0.8 mg; the yield was 40%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 15

At room temperature, 5.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 1.0 mL of 1,4-dioxane aqueous solution (20% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- in the suspension The amount of [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1, 4-times solubility in 4-dioxane aqueous solution), crystallization after stirring at 60 ° C for 7 days, centrifugation, the obtained solid was truly 60 ° C Air-drying for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3 -Crystalline form I of azetidincarboxylic acid. The yield was 4.9 mg; the yield was 84%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 16

At room temperature, add 4.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 4.7 mL of acetonitrile in water (40% by volume of water), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in acetonitrile aqueous solution at room temperature) The crystals were stirred at room temperature for 14 days to be crystallized, filtered, and the obtained solid was dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form I of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 3.0 mg; the yield was 64%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 17

At room temperature, add 3.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5 mL glass bottle. Group} -3-azetidinecarboxylic acid and 1.0 mL of chloroform in water (0.01% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in an amount of 5 times its solubility in aqueous chloroform at room temperature) The crystals were stirred at room temperature for 7 days to crystallize, and the obtained solid was vacuum-dried at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form I of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 2.3 mg; the yield was 77%. XRPD An X-ray powder diffraction pattern substantially the same as that in Fig. 1 was detected.

Example 18

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 3.6 mL of toluene aqueous solution (water content 0.1%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in 50 times its solubility in aqueous toluene at room temperature) It was crystallized by stirring at 40 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form I of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 28%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 19

At room temperature, 2.3 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 1.5 mL of an aqueous solution of dimethylarsine (water content 10%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is an aqueous solution of dimethylarsine at room temperature. 1.5 times the medium solubility), crystallization after stirring at 40 ° C for 7 days, filtration, and drying the obtained solid under vacuum at 60 ° C for 48 hours to obtain 1- {2-fluoro-4- [5- (4-isobutyl Crystalline Form I of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 26%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 20

At room temperature, 16.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 1.0 mL of tetrahydrofuran aqueous solution (water content 10%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4- (Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in tetrahydrofuran aqueous solution at room temperature) The crystals were stirred at room temperature for 7 days to crystallize, and the obtained solid was vacuum-dried at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form I of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 13.0 mg; the yield was 81%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 21

At room temperature, add 1.7mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 50mL single-necked flask. Methyl} -3-azetidinecarboxylic acid and 34.0 mL of methylcyclohexane in water (0.01% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5 in the suspension -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at room temperature in methylcyclohexyl 50 times the solubility in alkane aqueous solution), crystallized by stirring at 40 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-iso Form I of butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 59%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 22

At room temperature, add 1.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 50 mL single-necked bottle. } -3-azetidinecarboxylic acid and 38.0 mL of n-heptane aqueous solution (water volume content 0.1%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in the amount of its solubility in aqueous n-heptane at room temperature 50 times), crystallized by stirring at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 0.7 mg; the yield was 37%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 23

At room temperature, 2.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 1.0 mL tetrahydrofuran aqueous solution (50% by volume of water) and heated to 50 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is an amount of its solubility in the tetrahydrofuran aqueous solution at 50 ° C. 0.5 times), closed the water bath and naturally cooled to room temperature, and continued to stir for 10 hours to obtain a white solid, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Form I of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.2 mg; the yield was 48%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 24

Add 5.1mg 1- {2-Fluorine to a 20mL glass vial at room temperature -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 10.0 mL of an aqueous solution of tetrahydrofuran (aqueous 0.1% by volume) and heated to 40 ° C in a water bath and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole- The amount of 3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 times its solubility in the tetrahydrofuran aqueous solution at 40 ° C.) After closing the water bath and naturally cooling to room temperature, stirring was continued for 72 hours to obtain White solid, filtered, vacuum-dried at 60 ° C for 72 hours to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl of the present invention ] -Benzyl} -3-Acetidinecarboxylic acid, crystalline form I. The yield was 3.0 mg; the yield was 59%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 25

At room temperature, 7.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 1.0 mL tetrahydrofuran aqueous solution (0.01% by volume of water) and heated to 50 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is an amount of its solubility in the tetrahydrofuran aqueous solution at 50 ° C. 1 time), closed the water bath and naturally cooled to room temperature, and continued stirring for 1 hour to obtain a white solid, centrifuged, and dried under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Form I of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 3.7 mg; the yield was 47%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 26

At room temperature, add 1.6 mg of 1- {2-fluorine to a 20 mL glass vial -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 1.0 mL of tetrahydrofuran, sonicate for 5 minutes After the sample was completely dissolved (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidine The amount of pyridinecarboxylic acid is 1 times its solubility in tetrahydrofuran at room temperature), 10 mL of water was added dropwise to immediately obtain a white solid, stirred at room temperature for 10 hours, centrifuged, and dried under vacuum at 40 ° C for 1 hour to obtain the present invention Crystals of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid Type I. The yield was 1.0 mg; the yield was 62%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 27

At room temperature, add 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 150 mL single-necked bottle. Trifluorobutanolcarboxylic acid and 1.0 mL of ethanol in a trifluoroethanol solution (66% ethanol by volume), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- ( The amount of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is in a trifluoroethanol solution of ethanol at room temperature. 0.5 times the solubility), 100 mL of water was added dropwise thereto, and a white solid was immediately obtained, stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain the invention Crystalline Form I of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 1.3 mg; the yield was 87%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 28

At room temperature, add 1.7mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 50mL single-necked flask. } -3-azetidinecarboxylic acid and 28.0mL of 1,4-dioxane, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole- The amount of 3-yl] -benzyl} -3-azetidincarboxylic acid is 0.1 times its solubility in 1,4-dioxane at room temperature), and 1- {2-fluoro-4- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid in a 1,4-dioxane solution drop Add to 10.0 mL of water, immediately obtain a white solid, stir at 60 ° C for 0.5 hours, filter, and vacuum dry at 60 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form I. The yield was 0.7 mg; the yield was 41%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 29

At room temperature, add 1.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 20 mL glass vial. } -3-azetidinecarboxylic acid and 1.9 mL of dimethylarsine, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, The amount of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in dimethylarsine at room temperature), and 10 mL of water was added dropwise thereto, A white solid was obtained immediately, stirred at room temperature for 0.5 hours, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2, Crystalline form I of 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.4 mg; the yield was 74%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 30

At room temperature, add 1.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 20 mL glass vial. } -3-azetidinecarboxylic acid and 6.3mL aqueous isopropanol solution (50% by volume of water), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in this solution , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount of 1 times its solubility in an isopropanol aqueous solution at this temperature), using 0.45 microns (μm ) Organic filtration membrane filtration, the filtrate was placed in a 5 mL glass vial at 60 ° C. and the crystals were evaporated at 60 ° C., and the obtained solid was vacuum dried at 40 ° C. for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- ( Crystalline Form I of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 1.4 mg; the yield was 74%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 31

At room temperature, 1.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 10.0 mL tetrahydrofuran aqueous solution (water content is 0.1% by volume), and sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 times its solubility in tetrahydrofuran aqueous solution at room temperature ), Filtered with a 0.45 μm organic filter membrane, the filtrate was placed in a 20 mL glass vial and allowed to evaporate at room temperature for 3 days to crystallize, and the obtained solid was vacuum dried at room temperature for 24 hours to obtain the present invention -[5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- azetidinecarboxylic acid, crystalline form I. The yield was 0.4 mg; the yield was 24%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 32

At room temperature, 0.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. } -3-azetidinecarboxylic acid and 8.0 mL of acetone aqueous solution (water content is 0.01% by volume), and sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 in the solution , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.5 times its solubility in acetone aqueous solution at room temperature), filtered through a 0.45 μm organic filter membrane, The filtrate was placed in a 20-mL glass vial at room temperature for 1 day to evaporate and crystallize. The obtained solid was dried under vacuum at 60 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylbenzene). Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form I. The yield was 0.4 mg; the yield was 40%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in the first figure.

Example 33

At room temperature, 30.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Group} -3-azetidinecarboxylic acid and 3.0 mL of acetone (0.0000% by volume of water), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4 (-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in acetone at room temperature) The crystals were stirred at room temperature for 7 days to crystallize, and the obtained solid was dried under vacuum at room temperature for 72 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline form IV of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 27.5 mg; the yield was 91%.

The X-ray powder diffraction pattern is shown in Figure 6 and is in Form IV.

The PLM map is shown in Figure 7. Display: rod-like crystals.

DSC and TGA spectra are shown in Figure 8. It shows that the melting point of Form IV is 174 ° C; Form IV has no weight loss before 125 ° C, and the decomposition temperature is 183 ° C.

The DVS map is shown in Figure 9. Display: 20% RH ~ 80% RH weight The change is 1.6%.

The FT-IR spectrum is shown in Figure 10.

The above test results show that the crystal form IV is an anhydrous substance, has a good morphology, and is stable at high temperatures.

Example 34

At room temperature, add 3.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 20 mL glass bottle. Group} -3-azetidinecarboxylic acid and 7.4 mL of ethyl acetate (water content of 0.0000%), ultrasonication for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is its solubility in ethyl acetate at room temperature 50 times), crystallized by stirring at 40 ° C for 7 days, filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IV. The yield was 3.0 mg; the yield was 81%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 35

At room temperature, 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 150 mL glass bottle. } -3-azetidinecarboxylic acid and 100 mL of isopropyl acetate (volume content of 0.0000%), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used in isopropyl acetate at room temperature 1.5 times the solubility), stirred for 7 days at room temperature to crystallize, filtered, and dried the obtained solid under vacuum for 24 hours at room temperature to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylbenzene) Group) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 0.7 mg; the yield was 47%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 36

At room temperature, add 6.1mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5mL glass bottle. } -3-azetidincarboxylic acid and 1.0 mL of 1,4-dioxane (the volume content of water is 0.0001%), and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4 in the suspension -[5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at room temperature at 1 10-fold solubility in 4-dioxane), crystallize by stirring at 60 ° C for 7 days, filter, and dry the obtained solid under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 4.5 mg; the yield was 74%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 37

At room temperature, 1.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Group} -3-azetidinecarboxylic acid and 2.4 mL of acetonitrile (0.00005% by volume of water), sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4 (-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in acetonitrile at room temperature) , Crystallize by stirring at room temperature for 7 days, filter, and dry the obtained solid under vacuum at 60 ° C. for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline form IV of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.7 mg; the yield was 58%. XRPD inspection The X-ray powder diffraction pattern substantially the same as that in Fig. 6 was obtained.

Example 38

At room temperature, 5.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 1.0 mL of acetone in ethanol (50% by volume of acetone and 0.00005% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- { The amount of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is as follows: 10 times the solubility in an acetone-ethanol solution at room temperature), crystallized by stirring at room temperature for 14 days, filtered, and the resulting solid was dried under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [ Crystalline IV of 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 3.3 mg; the yield was 56%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 39

At room temperature, add 10.1-mg 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 0.5 mL of tetrahydrofuran in ethanol (50% by volume of tetrahydrofuran and 0.0002% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- { The amount of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is as follows: 10 times the solubility in tetrahydrofuran in ethanol solution at room temperature), stirred for 3 days at room temperature to crystallize, filtered, and dried the obtained solid under vacuum for 24 hours at room temperature to obtain the present invention 1- {2-fluoro-4- [ Crystalline IV of 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 8.1 mg; the yield was 80%. XRPD inspection The X-ray powder diffraction pattern substantially the same as that in Fig. 6 was obtained.

Example 40

At room temperature, add 1.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 0.3 mL of acetonitrile in ethanol (50% by volume of acetonitrile and 0.0002% by volume of water), and sonicated for 15 minutes to obtain a white suspension (1- { The amount of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is as follows: 10 times the solubility in acetonitrile in ethanol at room temperature), stirred for 7 days at room temperature to crystallize, filtered, and dried the obtained solid under vacuum for 24 hours at room temperature to obtain the present invention 1- {2-fluoro-4- [ Crystalline IV of 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.0 mg; the yield was 53%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 41

In a 5 mL glass vial, 10.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added at room temperature. Base} -3-azetidinecarboxylic acid and 1.0 mL of methanol (water content of 0.0001%) and heated to 60 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount of 1.0 at 60 ° C in the methanol Times), closed the water bath, naturally cooled to room temperature, and continued to stir for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Crystalline Form IV of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 8.7 mg; the yield was 86%. XRPD detection results in the same X-rays as in Figure 6. Line powder diffraction pattern.

Example 42

At room temperature, 9.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidincarboxylic acid and 2.0 mL ethanol (volume content of 0.0002%) and heated to 70 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount of 0.5 of its solubility in the ethanol at 70 ° C Times), closed the water bath and naturally cooled to room temperature, and continued to stir for 0.5 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Crystalline Form IV of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 8.1 mg; the yield was 84%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 43

At room temperature, 9.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 2.0 mL of isopropanol (water content of 0.0005% by volume) and heated to 75 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid was 75 ° C in the isopropanol 1 times the solubility), closed the water bath and naturally cooled to room temperature, and continued stirring for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 6.4 mg; the yield was 70%. XRPD detection results in the same X-rays as in Figure 6. Line powder diffraction pattern.

Example 44

At room temperature, 9.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidincarboxylic acid and 4.0 mL of n-propanol (0.001% by volume of water) and heated to 75 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 75 ° C in the n-propanol 0.5 times the solubility), closed the water bath and naturally cooled to room temperature, and continued stirring for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 5.6 mg; the yield was 62%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 45

At room temperature, 8.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Base} -3-azetidincarboxylic acid and 4.0 mL of n-butanol (volume content of 0.0001%) and heated to 80 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid was 80 ° C in the n-butanol 1 times the solubility), closed the water bath and naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-Fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 6.1 mg; the yield was 72%. XRPD detection results in the same X-rays as in Figure 6. Line powder diffraction pattern.

Example 46

At room temperature, 9.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 4.0 mL of 2-butanol (volume content of 0.0001%) and heated to 70 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid was 70 ° C at the 2-butanol 1 times the solubility in water), closed the water bath and naturally cooled to room temperature, and continued stirring for 72 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-Fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IV. The yield was 5.9 mg; the yield was 64%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 47

At room temperature, 3.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 1.0 mL of acetone (0.001% by volume of water) and heated to 50 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 of its solubility in acetone at 50 ° C. Times), closed the water bath, naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Crystalline Form IV of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.8 mg; the yield was 49%. XRPD detection results in the same X-ray powder as in Figure 6. End diffraction pattern.

Example 48

At room temperature, 4.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Base} -3-azetidincarboxylic acid and 3.0 mL of methyl ethyl ketone (volume content of 0.0001%) and heated to 40 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid has an solubility in the butanone at 40 ° C 0.5 times), closed the water bath and naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-iso Form IV of butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 1.7 mg; the yield was 42%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 49

At room temperature, 10.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 1.5 mL of ethyl acetate (volume content of 0.0002%) and heated to 60 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid was 60 ° C in the ethyl acetate. 1 times the solubility), closed the water bath and naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 9.7 mg; the yield was 89%. XRPD detection is basically the same as in Figure 6. The same X-ray powder diffraction pattern.

Example 50

At room temperature, 8.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 1.5 mL of isopropyl acetate (volume content of 0.0001%) and heated to 80 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5 The amount of-(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 80 ° C which is isopropyl acetate 0.8 times the solubility in the ester), closed the water bath and naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- Crystalline form IV of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 6.5 mg; the yield was 75%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 51

In a 5 mL glass vial, 10.3 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added at room temperature. Base} -3-azetidinecarboxylic acid and 1.0 mL of 1,4-dioxane (volume content of 0.0005%) and heated to 60 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4 The amount of-[5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 60 ° C at 1,4-dioxane solubility 1), closed the water bath and naturally cooled to room temperature and continued stirring for 10 hours to obtain a white solid, filtered, and dried under vacuum at room temperature for 48 hours to obtain the present invention 1- {2- Form IV of fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 9.5 mg; the yield was 92%. XRPD detection was obtained with Figure 6 This same X-ray powder diffraction pattern.

Example 52

At room temperature, 6.7 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidincarboxylic acid and 2.0 mL toluene (volume content of 0.0005%) and heated to 85 ° C in a water bath, and stirred until the sample was completely dissolved (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.8 in solubility in toluene at 85 ° C Times), closed the water bath, naturally cooled to room temperature, and continued stirring for 10 hours to obtain a white solid, which was filtered and dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl Crystalline Form IV of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 5.9 mg; the yield was 88%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 53

At room temperature, add 6.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 1.0 mL of ethanol in acetonitrile (25% by volume of ethanol and 0.0005% by volume of water) and heated to 70 ° C in a water bath and stirred until the sample is completely dissolved (1- { The amount of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid was 70 ° C Its solubility in the acetonitrile solution of ethanol is 1 times), after closing the water bath and naturally cooling to room temperature, stirring is continued for 10 hours to obtain a white solid, which is filtered and dried under vacuum at 40 ° C for 48 hours to obtain the present invention 1- {2 Form IV of -fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. Yield is 5.1 mg; yield was 76%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 54

At room temperature, add 1.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5 mL glass vial. } -3-Acetidinecarboxylic acid and 1.9 mL of dimethylarsine (volume content of 0.001%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 of its solubility in dimethyl sulfene at room temperature. Times), the dimethylarsine solution was added dropwise to a 5 mL glass bottle containing 1.9 mL of 2-butanol, stirred at room temperature for 72 hours, centrifuged, and dried under vacuum at 40 ° C. for 24 hours to obtain the present invention 1- {2-fluoro Form IV of 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 0.5 mg; the yield was 26%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 55

At room temperature, 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 1.0 mL of trifluoroethanol (volume content of 0.0005%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-iso Butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.5 times its solubility in trifluoroethanol at room temperature) The trifluoroethanol solution was added dropwise to a 20 mL glass bottle containing 10.0 mL of n-butanol, stirred at room temperature for 10 hours, centrifuged, and dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. Produce The amount was 0.3 mg; the yield was 20%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 56

At room temperature, 3.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. } -3-azetidinecarboxylic acid and 20.0mL tetrahydrofuran (the volume content of water is 0.001%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutyl The amount of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 0.1 times its solubility in tetrahydrofuran at room temperature). Add dropwise into a 150 mL single-necked flask containing 100.0 mL of ethyl acetate, stir at room temperature for 48 hours, centrifuge, and vacuum dry at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 0.6 mg; the yield was 19%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 57

At room temperature, 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidincarboxylic acid and 1.5 mL of dimethylarsine (volume content of 0.0005%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 of its solubility in dimethyl sulfene at room temperature. Times), the dimethylarsine solution was added dropwise to a 100 mL single-necked flask containing 50.0 mL of isopropyl acetate, stirred at room temperature for 10 hours, centrifuged, and dried under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2- Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid Crystalline form IV. The yield was 0.5 mg; the yield was 33%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 58

At room temperature, 1.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 2.0 mL of 1,4-dioxane (volume content of 0.0005%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1,4-dioxo at room temperature 1 times the solubility in hexacyclic), 1,4-dioxane solution was added dropwise to a 20 mL glass vial containing 10.0 mL of n-heptane, stirred at room temperature for 0.5 hours, filtered, and dried at 40 ° C under vacuum for 24 Hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidine Crystalline form IV. The yield was 0.7 mg; the yield was 58%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 59

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. Group} -3-azetidinecarboxylic acid and 6.0 mL of 1,4-dioxane (the volume content of water is 0.0008%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1,4-dioxo at room temperature 0.5 times the solubility in the six rings), 6.0 mL of isopropyl ether was added dropwise thereto, stirred at room temperature for 10 hours, filtered, and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. Yield is 1.0 mg; yield is 56%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 60

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. Group} -3-azetidinecarboxylic acid and 6.0 mL of 1,4-dioxane (volume content of 0.0005%), the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1,4-dioxo at room temperature 0.5 times the solubility in the six rings), 12.0 mL of n-propanol was added dropwise, stirred at room temperature for 10 hours, centrifuged, and dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 0.3 mg; the yield was 17%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 61

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 3.0 mL of methanol (0.0001% by volume of water), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount of 1 times its solubility in methanol at this temperature), It was filtered with a 0.45 μm organic filter membrane. The filtrate was placed in a 5 mL glass vial and crystallized by evaporation at room temperature. The obtained solid was dried under vacuum at room temperature for 1 hour to obtain the present invention 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidin Form IV of the carboxylic acid. The yield was 1.4 mg; the yield was 78%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 62

At room temperature, 1.6 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. } -3-azetidinecarboxylic acid and 4.0 mL ethanol (volume content of 0.0005%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount of 0.5 times its solubility in ethanol at this temperature), It was filtered through a 0.45 μm organic filter membrane, and the filtrate was placed in a 5 mL glass vial at 60 ° C. to volatilize and crystallize. The obtained solid was dried under vacuum at 40 ° C. for 24 hours to obtain the present invention 1- {2-fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form IV. The yield was 1.0 mg; the yield was 62%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 63

At room temperature, 1.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidincarboxylic acid and 5.0 mL of isopropanol (0.0005% by volume of water), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is based on its solubility in isopropanol at this temperature 0.8 times), filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial and crystallized at 60 ° C in an open state, and the obtained solid was dried under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro- 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form IV of azetidincarboxylic acid. The yield was 0.5 mg; the yield was 42%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 64

At room temperature, 1.3 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 4.0 mL of n-propanol (volume content of 0.0005%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is based on its solubility in n-propanol at this temperature 1x), filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial and crystallized by evaporation at room temperature, and the obtained solid was dried under vacuum at 40 ° C. for 48 hours to obtain the present invention 1- {2-fluoro- Crystalline form IV of 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.6 mg; the yield was 46%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 65

At room temperature, 1.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 5.0 mL of n-butanol (0.0001% by volume of water), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is based on its solubility in n-butanol at this temperature 1x), filtered with a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial at 60 ° C., and the crystals were volatilized at 60 ° C., and the obtained solid was vacuum-dried at 60 ° C. for 48 hours to obtain the present invention 1- {2-fluoro- 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form IV of azetidincarboxylic acid. The yield was 0.5 mg; the yield was 50%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 66

At room temperature, 0.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidincarboxylic acid and 5.0 mL of 2-butanol (volume content of 0.0001%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- ( The amount of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is its solubility in 2-butanol at this temperature 0.8 times), filtered with a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial and crystallized at 60 ° C in an open state, and the obtained solid was vacuum dried at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro Form IV of 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 0.6 mg; the yield was 75%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 67

At room temperature, 1.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 5.0 mL of methyl ethyl ketone (water content of 0.0001%), and sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount that is twice the solubility in methyl ethyl ketone at this temperature ), Filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial and crystallized by evaporation at room temperature, and the obtained solid was dried under vacuum at room temperature for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidin Form IV of the carboxylic acid. The yield was 0.6 mg; the yield was 60%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 68

At room temperature, 2.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Group} -3-azetidinecarboxylic acid and 4.0 mL of dimethylarsine (volume content of 0.0005%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is in dimethylsulfinium at this temperature 0.5 times the solubility), filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial at 60 ° C., and the crystals were volatilized at 60 ° C., and the obtained solid was dried under vacuum at 60 ° C. for 48 hours to obtain the present invention 1- {2- Form IV of fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 1.0 mg; the yield was 48%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 69

At room temperature, 0.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 5.0 mL of ethyl acetate (volume content of 0.0001%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- ( 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is based on its solubility in ethyl acetate at this temperature 1x), filtered with a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial at 60 ° C., and the crystals were volatilized at 60 ° C., and the obtained solid was dried under vacuum at 60 ° C. for 1 hour to obtain the present invention 1- {2-fluoro- 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form IV of azetidincarboxylic acid. The yield was 0.1 mg; the yield was 20%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 70

At room temperature, 0.4 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 4.0 mL of isopropyl acetate (volume content of 0.0002%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- The amount of (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is in isopropyl acetate at this temperature 1x solubility), filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 5 mL glass vial and crystallized at 40 ° C in an open, and the obtained solid was dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2- Form IV of fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 0.2 mg; the yield was 50%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 71

At room temperature, 3.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass vial. Methyl} -3-azetidinecarboxylic acid and 2.0 mL of tetrahydrofuran (volume content of 0.0005%), sonicated for 15 minutes to obtain a colorless clear solution (1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in an amount that is 1 times its solubility in tetrahydrofuran at this temperature), It was filtered through a 0.45 μm organic filter membrane. The filtrate was placed in a 5 mL glass vial and crystallized by evaporation at room temperature. The obtained solid was dried under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-Fluoro-4- [5 -(4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl Group} -3-azetidinecarboxylic acid crystalline form IV. The yield was 2.0 mg; the yield was 62%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 6.

Example 72

Take 5.9mg of crystal form I, directly place it on a hot stage that has been heated to 125 ° C for 1 hour, and crystallize, and then directly cool to room temperature for detection, to obtain the present invention 1- {2-fluoro-4- [5- (4-iso Form II of butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 5.9 mg; the yield was 100%.

The X-ray powder diffraction pattern is shown in Figure 16 and is in Form II.

The FT-IR spectrum is shown in Figure 17.

Example 73

Take 2.7mg of Form I, use DSC to heat up to 150 ° C at 10 ° C / min and hold for 0.5 hours to crystallize, directly cool to room temperature to detect, and obtain the present invention Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form II. The yield was 2.7 mg; the yield was 100%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 16.

Example 74

Take 3.2mg of Form I, use TGA to heat up to 110 ° C at 10 ° C / min and hold for 0.5 hours to crystallize, directly cool to room temperature and detect, to obtain the present invention 1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form II. The yield was 3.2 mg; the yield was 100%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 16.

Example 75

Take 5.3mg of crystal form I, directly place it in an oven at 100 ° C for 24 hours to crystallize, directly cool to room temperature and test, to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form II. The yield was 5.3 mg; the yield was 100%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 16.

Example 76

At room temperature, 4.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. } -3-azetidincarboxylic acid and 3.0 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.5 times its solubility in trifluoroethanol at room temperature), 3.0 mL of water was added dropwise, and immediately A white solid was obtained, stirred at room temperature for 0.5 hours, and filtered without drying to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadioxane Azol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form III. The yield was 3.1 mg; the yield was 69%.

The X-ray powder diffraction pattern is shown in FIG. 18 and is in Form III.

The FT-IR spectrum is shown in Figure 19.

Example 77

At room temperature, 4.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 1.4 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to Filled with 14mL of acetone In a 20 mL glass bottle, a white solid was immediately obtained, stirred at room temperature for 10 hours, filtered, and dried without obtaining the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 Form 2, III of 2,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 2.4 mg; the yield was 57%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 78

At room temperature, 6.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 2.0 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to In a 100-mL single-necked flask filled with 100 mL of ethyl acetate, a white solid was immediately obtained, stirred at room temperature for 72 hours, filtered, and dried to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutyl) Form III of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 1.3 mg; the yield was 22%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 79

At room temperature, add 3.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 200 mL single-necked bottle. Group} -3-azetidincarboxylic acid and 13 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2, The amount of 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 times its solubility in trifluoroethanol at room temperature), and 130 mL of isopropyl ether was added dropwise thereto, A white solid was obtained immediately, stirred at room temperature for 10 hours, and filtered without drying to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-ox Diazol-3-yl] -benzyl} -3-azetidine Form III of pyridinecarboxylic acid. The yield was 0.8 mg; the yield was 21%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 80

At room temperature, add 4.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 20 mL glass bottle. } -3-azetidinecarboxylic acid and 1.6 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 The amount of 4,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1 times its solubility in trifluoroethanol at room temperature), 16 mL of acetonitrile was added dropwise, and immediately A white solid was obtained, stirred at room temperature for 0.5 hours, and filtered without drying to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadioxane Azol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form III. The yield was 1.3 mg; the yield was 27%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 81

At room temperature, 5.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 2.0 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in trifluoroethanol at room temperature), and the trifluoroethanol solution is added dropwise to In a 50-mL single-necked bottle containing 20 mL of methyl tertiary butyl ether, a white solid was immediately obtained, stirred at room temperature for 10 hours, filtered, and dried to obtain the present invention 1- {2-fluoro-4- [5- ( 4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form III. The yield was 2.0 mg; the yield was 34%. XRPD detection results in the same X-ray powder as in Figure 18. End diffraction pattern.

Example 82

At room temperature, 4.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. } -3-azetidinecarboxylic acid and 15 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2, The amount of 4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 0.1 times its solubility in trifluoroethanol at room temperature), and filtered through a 0.45 μm organic filter membrane. The filtrate was placed in a 20-mL glass vial for 7 days at room temperature to evaporate and crystallize, without drying, to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form III. The yield was 0.3 mg; the yield was 7%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 83

At room temperature, add 5.2mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5mL glass bottle. Methyl} -3-azetidincarboxylic acid and 3.4 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.5 times its solubility in trifluoroethanol at room temperature), filtered through a 0.45 μm organic filter membrane, The filtrate was placed in a 5 mL glass vial at room temperature for 3 days without evaporation and crystallization, without drying, to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form III of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 2.1 mg; the yield was 40%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 84

At room temperature, add 6.1mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 5mL glass bottle. Methyl} -3-azetidincarboxylic acid and 2.0 mL of trifluoroethanol, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 , 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in trifluoroethanol at room temperature), filtered through a 0.45 μm organic filter membrane, The filtrate was placed in a 5 mL glass vial at room temperature for 1 day to volatilize and crystallize, without drying, to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, Crystalline Form III of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 3.8 mg; the yield was 62%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 18.

Example 85

At room temperature, 8.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-azetidincarboxylic acid and 4.0 mL of n-butanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) in the suspension The amount of -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 10 times its solubility in n-butanol at room temperature), stirring at 60 ° C Crystallize for 7 days, filter, and dry the obtained solid under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxazine Diazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form V. The yield was 6.1 mg; the yield was 76%.

The X-ray powder diffraction pattern is shown in FIG. 20 and is in the form V.

The FT-IR spectrum is shown in Figure 21.

Example 86

At room temperature, add 9.3mg of 1- {2-fluoro -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 31.0 mL of n-butanol, ultrasonic 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in this suspension } -3-Acetidinecarboxylic acid is used in an amount of 1.5 times its solubility in n-butanol at room temperature), stirred for 3 days at room temperature to crystallize, filtered, and dried the obtained solid under vacuum at 40 ° C for 48 hours, To obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinylcarboxyl Form V of the acid. The yield was 4.0 mg; the yield was 43%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 20.

Example 87

At room temperature, add 10.1-mg 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 1.0 mL of n-butanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) in the suspension -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in n-butanol at room temperature), stirred at 60 ° C Crystallize for 14 days, filter, and dry the obtained solid under vacuum at 60 ° C for 1 hour to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxalate of the present invention Diazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form V. The yield was 8.3 mg; the yield was 82%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 20.

Example 88

At room temperature, 4.4 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. } -3-azetidinecarboxylic acid and 20.0 mL of n-butanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro in the suspension The amount of -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is at room temperature. 1.1 times the solubility in n-butanol), crystallized by stirring at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4 -Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form V. The yield was 1.9 mg; the yield was 43%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 20.

Example 89

At room temperature, 7.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 1.0 mL of ethanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in ethanol at room temperature), and crystallized after stirring at room temperature for 7 days , Filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidincarboxylic acid, crystalline form VI. The yield was 6.3 mg; the yield was 80%.

The X-ray powder diffraction pattern is shown in Fig. 22, which is the crystal form VI.

Example 90

At room temperature, 2.4 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 2.0 mL of ethanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.5 times its solubility in ethanol at room temperature), and crystallized after stirring at room temperature for 3 days , Filtering, will get The obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl]- Form VI of benzyl} -3-azetidincarboxylic acid. The yield was 1.5 mg; the yield was 63%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 22.

Example 91

At room temperature, 80.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 2.0 mL of ethanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 50 times its solubility in ethanol at room temperature), and crystallized by stirring at 60 ° C for 14 days , Filtered, and the obtained solid was dried under vacuum at 60 ° C. for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidincarboxylic acid, crystalline form VI. The yield was 75.8 mg; the yield was 95%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 22.

Example 92

At room temperature, 1.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidinecarboxylic acid and 2.0 mL of ethanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.1 times its solubility in ethanol at room temperature), and crystallized after stirring at room temperature for 3 days , Filtered, and the obtained solid was dried under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidincarboxylic acid, crystalline form VI. Yield is 0.5 mg; yield is 28%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 22.

Example 93

In a 20 mL glass vial, 4.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added at room temperature. } -3-azetidincarboxylic acid and 4.0 mL of dimethylarsine, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, The amount of 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1 times its solubility in dimethylarsine at room temperature), using a 0.45 μm organic filter Filter, place the glass vial containing the filtrate in a closed atmosphere of 50mL water to 100mL for 14 days, wait for 40.0mL of water to diffuse into the dimethylarsine solution, filter after a large amount of solids, and dry the obtained solids under vacuum at 60 ° C In 24 hours, the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-acyl Form VII of butidinecarboxylic acid. The yield was 2.4 mg; the yield was 59%.

The X-ray powder diffraction pattern is shown in FIG. 23 and is in the form VII.

The FT-IR spectrum is shown in Figure 24.

Example 94

At room temperature, 2.0 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass vial. } -3-azetidincarboxylic acid and 4.0 mL of dimethylarsine, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1, 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.5 times its solubility in dimethylarsine at room temperature), using a 0.45 μm organic filter Filter and place the glass vial with the filtrate in a closed atmosphere of 20mL water to 100mL space for 7 days. 4.0mL of water was diffused into the dimethylarsine solution, and after a large amount of solid appeared, it was filtered, and the obtained solid was dried under vacuum at 40 ° C for 24 hours to obtain 1- {2-fluoro-4- [5- (4-isobutyl Form VII of phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.4 mg; the yield was 20%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 23.

Example 95

At room temperature, add 6.4 mg of Form VI and 0.8 mL of ethanol to a 5 mL glass bottle, and sonicate for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in ethanol at room temperature), at room temperature Crystallize after stirring for 7 days, filter, and dry the obtained solid under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- Form VIII of oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 5.8 mg; the yield was 91%.

The X-ray powder diffraction pattern is shown in FIG. 25 and is in the form VIII.

The FT-IR spectrum is shown in Figure 26.

Example 96

At room temperature, add 2.8 mg of Form VI and 2.3 mL of ethanol to a 5 mL glass bottle, and sonicate for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 1.5 times its solubility in ethanol at room temperature), at room temperature Crystallize after stirring for 3 days, filter, and dry the obtained solid under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- Form VIII of oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. Produce The amount was 1.5 mg; the yield was 54%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG.

Example 97

At room temperature, 39.8 mg of Form VI and 1.0 mL of ethanol were added to a 5 mL glass bottle and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in ethanol at room temperature), at 60 ° C Crystallize after stirring for 14 days, filter, and dry the obtained solid under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- Form VIII of oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 37.6 mg; the yield was 94%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG.

Example 98

At room temperature, add 1.8 mg of Form VI and 2.1 mL of ethanol to a 5 mL glass bottle and sonicate for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.1 times its solubility in ethanol at room temperature), at room temperature Crystallize after stirring for 3 days, filter, and dry the obtained solid under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4- Form VIII of oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.3 mg; the yield was 17%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG.

Example 99

At room temperature, add 2.9mg of 1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid and 1.0 mL of isopropanol, sonicated for 15 minutes to obtain a white suspension (the suspension 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid in liquid The amount used is 10 times its solubility in isopropanol at room temperature), crystallized by stirring at room temperature for 7 days, filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro Form IX of 4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid. The yield was 2.4 mg; the yield was 83%.

The X-ray powder diffraction pattern is shown in FIG. 27 and is in the form IX.

The FT-IR spectrum is shown in Figure 28.

Example 100

At room temperature, 4.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. } -3-azetidinecarboxylic acid and 10.0 mL of isopropanol, and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) in the suspension The amount of -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1.5 times its solubility in isopropanol at room temperature), stirring at room temperature Crystallize for 3 days, filter, and dry the obtained solid under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxazine Diazol-3-yl] -benzyl} -3-azetidininecarboxylic acid, Form IX. The yield was 1.5 mg; the yield was 33%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in FIG. 27.

Example 101

At room temperature, 15.2 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. } -3-azetidinecarboxylic acid and 1.0mL isopropanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole- The amount of 3-yl] -benzyl} -3-azetidinecarboxylic acid is 50 times its solubility in isopropanol at room temperature), crystallize after stirring at 60 ° C for 14 days, and filter the obtained solid Drying under vacuum at 60 ° C for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} Crystalline Form IX of 3-Azidine. The yield was 11.9 mg; the yield was 78%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in FIG. 27.

Example 102

At room temperature, 3.3 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 20 mL glass bottle. } -3-azetidinecarboxylic acid and 10.0 mL of isopropanol, and sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) in the suspension -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.1 times its solubility in isopropanol at room temperature), and stirred at room temperature Crystallize for 3 days, filter, and dry the obtained solid under vacuum at room temperature for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-ox Diazol-3-yl] -benzyl} -3-azetidininecarboxylic acid, Form IX. The yield was 1.2 mg; the yield was 36%. The XRPD detection yielded an X-ray powder diffraction pattern substantially the same as that in FIG. 27.

Example 103

At room temperature, add 6.1mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 20mL glass bottle. Group} -3-azetidinecarboxylic acid and 10.0mL of 1,4-dioxane, and the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) The amount of -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is room temperature Its solubility in 1,4-dioxane is doubled), filtered through a 0.45 μm organic filter membrane, and the filtrate is placed in a 20 mL glass vial and crystallized at room temperature for 7 days. Drying under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} Crystalline Form X of 3-Azidine. The yield was 5.7 mg; the yield was 93%.

The X-ray powder diffraction pattern is shown in FIG. 29 and is in the form X.

The FT-IR spectrum is shown in Figure 30.

Synthesis Example 104

At room temperature, add 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 20 mL glass bottle. } -3-azetidincarboxylic acid and 5.0 mL of 1,4-dioxane, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro-4- [5- (4-isobutylphenyl) The amount of -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 0.5 times its solubility in 1,4-dioxane at room temperature) , Filtered through a 0.45 μm organic filter membrane, the filtrate was placed in a 20 mL glass vial and crystallized at room temperature for 1 day, and the obtained solid was dried under vacuum at 40 ° C. for 24 hours to obtain the present invention 1- {2-fluoro-4 -[5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form X. The yield was 0.5 mg; the yield was 33%. XRPD detection yielded the same X-ray powder diffraction pattern as in Figure 29.

Example 105

At room temperature, add 5.9 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 100 mL single-necked flask. } -3-azetidinecarboxylic acid and 100.0mL of 1,4-dioxane, the sample was completely dissolved after 5 minutes of sonication (1- {2-fluoro The amount of -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is at room temperature. 0.1 times the solubility in 1,4-dioxane), filtered through a 0.45 μm organic filter membrane, and the filtrate was placed in a 100 mL single-necked flask at 60 ° C for 3 days to open and crystallize. Drying for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form A of azetidincarboxylic acid. The yield was 2.1 mg; the yield was 36%. XRPD detection yielded the same X-ray powder diffraction pattern as in Figure 29.

Example 106

At room temperature, add 10.2mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 150 mL single-necked flask. Methyl} -3-azetidincarboxylic acid and 100.0 mL of toluene, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in toluene at room temperature), and crystallized after stirring at room temperature for 7 days , Filtered, and the obtained solid was dried under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidininecarboxylic acid, Form XI. The yield was 7.4 mg; the yield was 73%.

The X-ray powder diffraction pattern is shown in Fig. 31, which is the crystal form XI.

The FT-IR spectrum is shown in Figure 32.

Example 107

At room temperature, add 1.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 150 mL single-necked bottle. Methyl} -3-azetidinecarboxylic acid and 100.0 mL of toluene, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro in the suspension The amount of -4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is at room temperature. 1.5 times the solubility in toluene), crystallized by stirring at room temperature for 3 days, filtered, and the obtained solid was dried under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-iso Form XI of butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid. The yield was 0.5 mg; the yield was 33%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 31.

Example 108

At room temperature, 2.5 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 5.0 mL of toluene, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in toluene at room temperature), and crystallized by stirring at 60 ° C for 14 days , Filtered, and the obtained solid was dried under vacuum at 60 ° C. for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -benzyl} -3-azetidininecarboxylic acid, Form XI. The yield was 1.9 mg; the yield was 76%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 31.

Example 109

At room temperature, add 1.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl in a 150 mL single-necked bottle. Methyl} -3-azetidincarboxylic acid and 100.0 mL of toluene, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl) -1 in the suspension , 2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.1 times its solubility in toluene at room temperature), and stirred at room temperature for 3 days. Crystal, filtered, and the obtained solid was dried under vacuum at room temperature for 24 hours to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole- 3-yl] -benzyl} -3-azetidininecarboxylic acid, Form XI. The yield was 0.2 mg; the yield was 22%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 31.

Example 110

At room temperature, add 12.1 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 2.0 mL of anhydrous methanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 10 times its solubility in anhydrous methanol at room temperature), and stirred at room temperature for 7 days Crystallize, filter, and dry the obtained solid under vacuum at room temperature for 48 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form XII. The yield was 9.4 mg; the yield was 78%.

The X-ray powder diffraction pattern is shown in Figure 11 and is in crystal form XII.

The PLM map is shown in Figure 12. Display: Fine crystals.

DSC and TGA spectra are shown in Figure 13. It shows that crystal form XII has a wide endothermic peak (solvent peak) at 25 ~ 90 ℃, and the sample after dehydration melts and decomposes at 148 ℃; crystal form XII loses 1.7% of surface solvent before 100 ℃, and the decomposition temperature is 142 ℃. The decomposition temperature was 142 ° C.

The DVS map is shown in Figure 14. Display: The weight change from 20% RH to 80% RH is 1.3%.

The FT-IR spectrum is shown in Figure 15.

The above test results show that the crystal form XII is an anhydrous substance and is not easy to absorb moisture.

Example 111

At room temperature, 1.4 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 1.5 mL of anhydrous methanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl)- The amount of 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is 1.5 times its solubility in anhydrous methanol at room temperature), and stirred at room temperature for 3 days Crystallize, filter, and dry the obtained solid under vacuum at 40 ° C for 1 hour to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form XII. The yield was 0.6 mg; the yield was 43%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 11.

Synthesis Example 112

At room temperature, 29.8 mg of 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl was added to a 5 mL glass bottle. Methyl} -3-azetidincarboxylic acid and 1.0 mL of anhydrous methanol, sonicated for 15 minutes to obtain a white suspension (1- {2-fluoro-4- [5- (4-isobutylphenyl)- 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is used at 50 times its solubility in anhydrous methanol at room temperature), and stirred at 60 ° C for 14 days Crystallize, filter, and dry the obtained solid under vacuum at 60 ° C for 24 hours to obtain the present invention 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole -3-yl] -benzyl} -3-azetidincarboxylic acid, crystalline form XII. The yield was 25.1 mg; the yield was 84%. The XRPD detection obtained the X-ray powder diffraction pattern substantially the same as that in FIG. 11.

Comparative Example 1

Take 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidin of the present invention Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI of carboxylic acid And the amorphous prepared according to Preparation Example 1 was subjected to a competitive crystal slurry test.

The specific operations are as follows:

(1) Take 2mg each of Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI and amorphous, respectively in isopropanol, water, ethanol aqueous solution (volume ratio of ethanol and water are 1: 1, 1: 5, 1:10 and 1: 100 respectively), ethanol, acetone aqueous solution (acetone and The volume ratio of water was 1: 1, 1: 5, 1:10, and 1: 100 respectively) and a suspension was formed in acetone. After stirring at room temperature for 3 days, XRPD characterization and comparison were performed.

(2) Take 5mg of Form IV and Form XII each to form a suspension in water and acetone, and then perform XRPD characterization and comparison after stirring at room temperature for 3 days.

(3) Take 5mg of Form I and Form XII each to form a suspension in ethanol, and then perform XRPD characterization comparison after stirring at room temperature for 3 days.

The results are shown in Table 1 and found:

(1) At room temperature, Form I is the most stable form in an aqueous system, and Form IV is the most stable form in a pure organic solvent.

(2) At room temperature, crystal form XII and crystal form IV are more stable for crystal form XII in water, and crystal form XII and form IV are more stable for crystal form IV in acetone.

Table 1: Statistics of competitive slurry experiments

Comparative Example 2

The crystal form I, crystal form IV and crystal form XII of the present invention were taken and subjected to a stability placement test.

The specific operations are as follows: Take 5mg of each of Form I, Form IV and Form XII, and place them open at room temperature dryer, room temperature, room temperature-97% RH, room temperature-75% RH or room temperature-44% RH. XRPD characterization comparison was performed after 1 month.

The results are shown in Table 2. It was found that after being left for one month in a room temperature dryer, room temperature open, room temperature-97% RH, room temperature-75% RH or room temperature-44% RH, the crystal form I, crystal Both Form IV and Form XII remain unchanged.

Comparative Example 3

Take Form I, Form IV, Form XII, Form II, Form III, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form X XI and the amorphous material prepared according to Preparation Example 1, using pharmaceutically acceptable excipients commonly used in the art, according to the conventional method for preparing capsules, capsules of each crystal form or amorphous substance were prepared, and then A comparison test of the crystal form change and dissolution of the capsules at 0 days and 6 months was performed.

The specific operation is as follows: using the paddle method, using water as the dissolution medium, the temperature is 37 ° C, the rotation speed of the stirring paddle is 50 rpm, and the capsules (without the capsule shell) are stirred with 900 mL of pure water to form suspensions. 20 mL samples were taken at 10 minutes, 20 minutes, 40 minutes, 60 minutes, 120 minutes, and 24 hours. After each sampling, 20 mL was taken up, and the concentration of the samples at each time point was determined by HPLC.

The experimental results show that: (1) After the capsules are left for 6 months, the amorphous substance and the crystal form II, crystal form III, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form of the present invention In capsules of Form IX, Form X, and Form XI, part or all of the form has changed, while in the capsules of Form I, Form IV, and Form XII of the present invention, the form remains unchanged , It shows that the crystal form I, crystal form IV and crystal form XII of the present invention have good crystal form stability; (2) the amorphous substance and the crystal form II, crystal form III, crystal form V, crystal form VI, The dissolution of capsules of Form VII, Form VIII, Form IX, Form X, and Form XI at 0 and 6 months has changed due to the change of their crystalline form, which will lead to inferior product quality. Stability, which in turn affects the efficacy. The dissolution rate of the capsules of Form I, Form IV and Form XII of the present invention is basically unchanged at 0 days and 6 months. Therefore, Form I, Form IV and Form XII of the present invention are more suitable for preparation. Application of the product.

All patent documents and non-patent publications cited in this specification are incorporated herein by reference in their entirety.

The above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited to this. Any person skilled in the art can make changes or changes that come to mind without creative labor within the technical scope disclosed by the present invention. Replacement should be covered by the protection scope of the present invention.

Claims (15)

One structural formula is 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form I of azetidine carboxylic acid, Wherein, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the crystal form I at the diffraction angle 2θ is 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 There are characteristic peaks at ° and 18.6 ± 0.2 °. The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form I at a diffraction angle 2θ is 4.8 ± 0.2 °, 5.5 ± 0.2 °, 8.2 ± 0.2 °, 10.1 ± 0.2 There are characteristic peaks at °, 11.1 ± 0.2 °, 12.1 ± 0.2 °, 15.0 ± 0.2 °, 17.0 ± 0.2 °, 18.6 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 °, and 27.0 ± 0.2 °. The crystal form I according to claim 2, wherein the X-ray powder diffraction pattern of the crystal form I has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position: A method for preparing the crystal form I according to any one of claims 1-3, wherein the preparation method adopts any one of the following methods: (1) 1- {2-fluoro-4- [5 -(4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid forms a suspension in the following solvent system and crystallizes by stirring The precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} Crystalline form I of -3-azetidincarboxylic acid; wherein the solvent system is selected from water or a mixture of water and an organic solvent; the organic solvent is selected from a C ₁ to C ₄ alcohol, a C ₅ to C ₆ ether, C ₃ ~ C ₄ ketones, ethyl acetate, nitromethane, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chloroform, toluene, dimethyl sulfene, C ₇ alkanes and mixtures thereof; said The volume of water in the mixture of water and organic solvent is at least 0.01%; 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3- The amount of the group] -benzyl} -3-azetidinecarboxylic acid is 1.1 to 50 times its solubility in the solvent system at the operating temperature; the crystallization temperature is from room temperature to 60 ° C; Operating temperature Room temperature; the crystallization time is 3-14 days; (2) at a certain temperature, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is formed into a solution in a mixed system of water and tetrahydrofuran, cooled and stirred for crystallization, and the precipitated crystals are separated and dried to obtain 1- {2-Fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-Acetidinecarboxylic acid, crystalline form I Wherein the volume content of water in the mixed system of water and tetrahydrofuran is 0.01% to 50%; in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl)- The amount of 1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the mixed system at a certain temperature; the certain The temperature is 40 ° C to 50 ° C; the temperature after cooling is room temperature; the crystallization time is 0.5 to 72 hours; (3) to 1- {2-fluoro-4- [5- (4-iso Butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is added to a solution formed in an organic solvent, and the solution is stirred and crystallized. The crystals were separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3 -Crystalline form I of azetidine carboxylic acid; wherein the organic solvent is selected from the group consisting of ethanol and trifluoroethanol, tetrahydrofuran, 1,4-dioxane, dimethylarsine, or mixtures thereof; the water and organic The volume ratio of the solvent is 1: 1 to 50: 1; in the solution, 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole- The amount of 3-yl] -benzyl} -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the organic solvent at the operating temperature; the operating temperature is room temperature; the crystallized The temperature is from room temperature to 60 ° C; the crystallization time is 0.5 to 72 hours; (4) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2, A solution of 4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in a mixed system of water and an organic solvent is evaporated and crystallized. The precipitated crystals are separated and dried to obtain 1- {2 Form I of -fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid; wherein The organic solvent is selected from the group consisting of isopropanol, acetone, tetrahydrofuran, or a mixture thereof; the volume content of water in the mixture of water and organic solvent is 0.01% to 50%; 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazole-3- The amount of] -benzyl} -3-azetidinecarboxylic acid is 0.1 to 1 times its solubility in the solvent system at the operating temperature; the operating temperature is room temperature; and the crystallization temperature is room temperature. Temperature to 60 ° C; the crystallization time is 1 to 7 days; in the method for preparing (1) to (4) crystal form I, the drying temperature is from room temperature to 60 ° C; and the drying time It is 1 ~ 48 hours. One structural formula is 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Form IV of azetidincarboxylic acid, Wherein, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the crystal form IV at the diffraction angle 2θ is 4.8 ± 0.2 °, 9.0 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 There are characteristic peaks at ° and 17.7 ± 0.2 °. The crystal form IV according to claim 5, wherein the X-ray powder diffraction pattern of the crystal form IV at a diffraction angle 2θ is 4.8 ± 0.2 °, 9.0 ± 0.2 °, 9.8 ± 0.2 °, 12.4 ± 0.2 There are characteristic peaks at °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 ° and 19.8 ± 0.2 °. The crystal form IV according to claim 6, wherein the X-ray powder diffraction pattern of the crystal form IV has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position: A method for preparing the crystal form IV according to any one of claims 5-7, wherein the preparation method adopts any one of the following methods: (1) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid was suspended in an organic solvent system as follows, The crystals were stirred and separated, and the precipitated crystals were separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl]- Form IV of benzyl} -3-azetidinecarboxylic acid; wherein the organic solvent is selected from the group consisting of C ₂ -C ₃ alcohol, acetone, C ₄ -C ₅ ester, tetrahydrofuran, 1,4-dioxane , Acetonitrile and mixtures thereof; after the organic solvent is dried, the volume content of water in the organic solvent is less than 0.001%; 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2 The amount of 4,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid is 1.1 to 50 times its solubility in the solvent system at the operating temperature; the operating temperature is room temperature. The crystallization temperature is from room temperature to 60 ° C; the crystallization time is 3-14 days; (2) at a certain temperature, 1- {2-fluoro-4- [5- (4- Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-Azidine carboxylic acid is formed into a solution in an organic solvent, cooled and stirred for crystallization, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutylphenyl) ) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid, crystalline form IV; wherein the organic solvent is selected from the group consisting of C ₁ to C ₄ alcohols, C ₃ ~ C ₄ ketone, C ₄ ~ C ₅ ester, 1,4-dioxane, acetonitrile, toluene and mixtures thereof; the organic solvent is dried, and the volume content of water in the organic solvent is less than 0.001%; the solution In 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid The amount used is 0.1 to 1 times its solubility in the organic solvent at a certain temperature; the certain temperature is 40 ° C to 80 ° C; the cooled temperature is room temperature; and the crystallization time is 0.5 to 72 hours; (3) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- A slightly soluble or insoluble solvent is added to the solution of azetidinecarboxylic acid in a soluble solvent, and the crystals are stirred and crystallized, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-iso Butylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidin Form IV acid; wherein said soluble solvent is selected from trifluoroethanol, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide or mixtures thereof; sparingly soluble or insoluble in the solvent is selected from C ₃ ~ C ₄ alcohol, C ₄ ~ C ₅ ester, isopropyl ether, n-heptane or a mixture thereof; the slightly soluble or insoluble solvent is selected from n-propanol, n-butanol, 2-butanol, ethyl acetate, acetic acid Propyl ester, isopropyl ether or n-heptane; the solvents are all dried, and the volume content of water in the organic solvent is less than 0.001%; the volume ratio of the slightly soluble or insoluble solvent to the soluble solvent is 1: 1 to 50 : 1; 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3 in the solution -The amount of azetidine carboxylic acid is 0.1 to 1 times its solubility in the soluble solvent at the operating temperature; the operating temperature is room temperature; the crystallization temperature is from room temperature to 60 ° C; The crystallization time is 0.5 ~ 72 hours; (4) 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl A solution of] -benzyl} -3-azetidinecarboxylic acid in an organic solvent is evaporated and crystallized, and the precipitated crystals are separated and dried to obtain 1- {2-fluoro-4- [5- (4-isobutyl benzene ) -1,2,4-oxadiazol-3-yl] - benzyl} -3 Form IV azetidine carboxylic acid; wherein said organic solvent is selected from C ₁ ~ C ₄ alcohols, C ₄ ~ C ₅ ester, methyl ethyl ketone, tetrahydrofuran, dimethylarsine or a mixture thereof; the organic solvent is dried, and the volume content of water in the organic solvent is less than 0.001%; 1- {2-fluoro-4- [5- ( The amount of 4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidincarboxylic acid is its solubility in the solvent system at the operating temperature The operating temperature is room temperature; the crystallization temperature is from room temperature to 60 ° C; the crystallization time is 1 to 7 days; the above-mentioned (1) to (4) crystal form IV In the preparation method, the drying temperature is from room temperature to 60 ° C; and the drying time is from 1 to 48 hours. One structural formula is 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3- Crystalline form XII of azetidincarboxylic acid, Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form XII at the diffraction angle 2θ is 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 °, and 19.3 ± 0.2 There are characteristic peaks at °. The crystal form XII according to claim 9, wherein the X-ray powder diffraction pattern of the crystal form XII at a diffraction angle 2θ is 6.3 ± 0.2 °, 9.5 ± 0.2 °, 12.7 ± 0.2 °, 18.0 ± 0.2 There are characteristic peaks at °, 19.3 ± 0.2 °, 21.8 ± 0.2 °, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 °, and 25.7 ± 0.2 °. The crystal form XII according to claim 10, wherein the X-ray powder diffraction pattern of the crystal form XII has a characteristic peak and its relative intensity at a diffraction angle 2θ of the following position: A method for preparing the crystal form XII according to any one of claims 9-11, wherein the preparation method is prepared by the following method: 1- {2-fluoro-4- [5- (4-isobutyl Phenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid in suspension in anhydrous methanol to form a suspension, crystallize by stirring, and separate the precipitated crystals and dry To give 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl} -3-azetidinecarboxylic acid Crystalline form XII; wherein the 1- {2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzyl}- The amount of 3-azetidinecarboxylic acid is 1.1 to 50 times its solubility in anhydrous methanol at the operating temperature; the crystallization temperature is from room temperature to 60 ° C; the operating temperature is room temperature; the crystallization The crystallizing time is 3-14 days. In the method for preparing the crystal form XII, the drying temperature is from room temperature to 60 ° C; and the drying time is 1 to 48 hours. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of one or more crystals selected from the group consisting of the crystal form I according to any one of claims 1-3, and the crystal according to any one of claims 5-7. Form IV, Form XII according to any one of claims 9-11, Form I obtained according to the preparation method described in claim 4, Form IV obtained according to the preparation method described in claim 8, or upon request Form XII obtained by the preparation method according to item 12, and at least one pharmaceutically acceptable carrier. Form I according to any of claims 1-3, Form IV according to any of claims 5-7, Form XII according to any of claims 9-11, according to The crystalline form I obtained by the preparation method described in claim 4, the crystalline form IV obtained by the preparation method described in claim 8, or the crystalline form XII obtained by the preparation method described in claim 12, is used for the preparation of a treatment by the S1P1 receptor. Of medicament for a disease or condition. A pharmaceutical composition for treating and / or preventing a disease or condition mediated by the S1P1 receptor, said pharmaceutical composition comprising a therapeutic and / or preventive effective amount of one or more selected from any one of claims 1-3 The crystal form I according to claim 4, the crystal form IV according to any of claims 5-7, the crystal form XII according to any of claims 9-11, obtained according to the preparation method according to claim 4. Form I, Form IV obtained according to the preparation method described in claim 8 or Form XII obtained according to the preparation method described in claim 12, and at least one pharmaceutically acceptable carrier.